Mysterio signed with Paul Heyman's Extreme Championship Wrestling (ECW) in 1995. He debuted in September at Gangstas Paradise, defeating Psicosis, who was also making his ECW debut. A feud between the two began, which included a two out of three falls match and a Mexican Death match. Mysterio also had a series of matches with ECW-newcomer Juventud Guerrera during the first half of 1996.
Mysterio made his World Championship Wrestling (WCW) debut on June 16, 1996, at The Great American Bash, challenging Dean Malenko for the WCW Cruiserweight Championship, which Malenko retained by winning. In July at Bash at the Beach, he defeated longtime rival Psicosis in a number one contender's match to earn another opportunity at the Cruiserweight title. The next night, on the July 8 episode of WCW Monday Nitro, he defeated Malenko to win his first Cruiserweight Championship. He reigned as champion for three months, which included title defenses against the likes of Ultimate Dragon, Malenko, and Super Caló before he lost the title to Malenko at Halloween Havoc. Following his Cruiserweight Championship reign, Mysterio challenged Ultimate Dragon, but was unsuccessful in his title match at World War 3 in November.
In early 1997, he feuded with Prince Iaukea over the WCW World Television Championship. Mysterio was defeated in his title match against Iaukea at SuperBrawl VII after Lord Steven Regal attacked him. Mysterio also lost a championship rematch at Uncensored in March. Mysterio soon began a feud with the New World Order (nWo), which culminated when he lost a Mexican Death match to nWo member Konnan at Road Wild in August. Mysterio then became involved in a feud with his real-life friend and Cruiserweight Champion Eddie Guerrero. He defeated Guerrero in a Title vs. Mask match at Halloween Havoc to win the Cruiserweight Championship for the second time. On the November 10, 1997, episode of Nitro, he lost the title back to Guerrero. They had a rematch at World War 3, which Mysterio also lost.
On the January 15, 1998, episode of WCW Thunder, Mysterio defeated Juventud to win his third Cruiserweight Championship, but lost it nine days later to Chris Jericho at Souled Out. After the match, Jericho continued the beating by using a toolbox he found at ringside. This storyline was used to cover Mysterio's need for a knee operation that kept him out of the ring for six months. He made his return at Bash at the Beach, where he defeated Jericho for his fourth Cruiserweight championship. The next night, however, the result was overturned and the belt returned to Jericho due to Dean Malenko interfering. Later that year, Eddie Guerrero formed a Mexican stable known as the Latino World Order (LWO) (a spin off of New World Order) that included nearly every luchador in the promotion. Mysterio continually refused to join and feuded with Guerrero and the LWO members, including winning a match against longtime rival and LWO member Psicosis in a match at Road Wild. He was finally forced to join the group after losing a match to Eddie Guerrero. Mysterio's on-and-off tag team partner Billy Kidman joined him during the feud with LWO, wrestling against the LWO despite Mysterio being a part of the group. His alliance with Kidman was formed after Mysterio helped Kidman defeat Juventud for the Cruiserweight Championship at World War 3. Mysterio went up against Kidman for the title at Starrcade but was unsuccessful winning back the title in a triangle match that also involved Juventud. Kidman once again defeated Mysterio for the title at Souled Out in a fatal four-way match that also included Psicosis and Juventud.
In 1999, after the two factions of nWo reformed, they demanded that the LWO disband. Mysterio refused to take off his LWO colors and was attacked by the nWo as a result. This led to a match at SuperBrawl IX where Mysterio and tag partner Konnan lost a "Hair vs. Mask match" against Kevin Nash and Scott Hall, forcing Mysterio to remove his mask.
Mysterio later became a "giant killer" by defeating large opponents such as Kevin Nash, Bam Bam Bigelow, and Scott Norton. He faced Nash at Uncensored in a match where Lex Luger interfered and helped Nash in winning the match.
The next night on the March 15 Nitro, he defeated Billy Kidman to win his fifth Cruiserweight Championship. On the March 22 Spring Breakout episode of Nitro, Mysterio got his first shot at the WCW World Heavyweight Championship against champion Ric Flair when the names of (allegedly) nearly everyone in the company were put into a hat and a lottery was held. El Dandy was the lottery winner, but he was injured, and Mysterio took the shot instead. The match ended with a disqualification win for Flair, even though Arn Anderson's interference on Flair's behalf should have theoretically disqualified Flair. The following week, Mysterio and Kidman teamed with each other and defeated Flair's Four Horsemen stablemates Chris Benoit and Dean Malenko to win the WCW World Tag Team Championship, making Mysterio a double champion. Mysterio successfully defended his Cruiserweight Championship against his tag team partner Kidman at Spring Stampede before losing the title on the April 19 episode of Nitro to Psicosis in a Fatal Four-Way match that also involved Juventud Guerrera and Blitzkrieg. On the following episode of Nitro, he defeated Psicosis to win his fifth Cruiserweight Championship. At Slamboree, Mysterio and Kidman lost the World Tag Team titles to Raven and Perry Saturn in a Triangle match, also involving former champions Benoit and Malenko.
In mid-1999, Mysterio and Konnan joined Master P's No Limit Soldiers, and began feuding with The West Texas Rednecks. At The Great American Bash, they defeated Rednecks members Curt Hennig and Bobby Duncum Jr. in a tag team match. At Bash at the Beach, they defeated the Rednecks in a four-on-four elimination tag team match when Mysterio pinned Hennig. After Master P's departure from WCW, Mysterio formed a stable with Eddie Guerrero and Billy Kidman known as the Filthy Animals, thus turning heel in the process. This was Mysterio's only heel turn in his career. The three wrestlers soon began a feud with the Dead Pool. The Filthy Animals defeated the Dead Pool in a six-man tag team match at Road Wild and at Fall Brawl. On the August 19 episode of Thunder, Mysterio lost the Cruiserweight Title to Lenny Lane.
On the October 18 episode of Nitro, Mysterio and Konnan teamed up together to defeat Harlem Heat for the World Tag Team Championship. Mysterio, however, was injured during the match and was sidelined as a result. Billy Kidman substituted for Mysterio and teamed with Konnan during their title defense against Harlem Heat and The First Family, in which the Filthy Animals went on to lose the title back to Harlem Heat. Mysterio returned in early 2000 and remained a steady performer, eventually joining the New Blood faction in early 2000 opposing the Millionaire's Club. On the August 14 episode of Nitro, Mysterio and Juventud defeated The Great Muta and Vampiro to win the World Tag Team Championship. They were stripped of the title after Ernest Miller pinned Disco Inferno with the stipulation that if he pinned Disco, Mysterio and Guerrera would be stripped of the title. The Filthy Animals then feuded with The Natural Born Thrillers in the fall of the year. At Fall Brawl, the Filthy Animals fought the Thrillers to a no contest in an Elimination tag team match. Mysterio reformed his tag team with Kidman and the two challenged for the World Tag Team Championship in a Triangle match at Halloween Havoc, facing the champions Natural Born Thrillers and The Boogie Knights, where the Thrillers retained.
At the beginning of 2001, the Filthy Animals feuded with Team Canada, to whom they lost in a Penalty Box match at Sin. At SuperBrawl Revenge, Mysterio unsuccessfully challenged Chavo Guerrero Jr. for the Cruiserweight Title. Kidman and Mysterio participated in a Cruiserweight tag team tournament for the newly created WCW Cruiserweight Tag Team Championship and advanced to the final round where they ended up losing to Elix Skipper and Kid Romeo. On the final episode of Nitro on March 26, they defeated Skipper and Romeo in a rematch to win the Cruiserweight Tag Team Titles before WCW was sold to the World Wrestling Federation (WWF).
In June 2002, Mysterio signed with World Wrestling Entertainment (WWE), and promos that hyped his debut began airing. The "Jr." was dropped from his name and was billed simply as Rey Mysterio. At the insistence of Vince McMahon, Mysterio agreed to wear his mask again.
Mysterio made his WWE debut on the July 25, 2002, episode of SmackDown! as a fan favorite in a match against Chavo Guerrero, which Mysterio won. He eventually began a feud with Kurt Angle, which culminated in a match at SummerSlam that Angle won after forcing Mysterio to submit to the ankle lock. He later formed a tag team with Edge; the two participated in a tournament for the newly created and SmackDown!-exclusive WWE Tag Team Championship. They lost to Kurt Angle and Chris Benoit in the finals of the tournament at No Mercy. After they failed to win the title, Mysterio and Edge defeated Los Guerreros in a number one contender's match on the October 24 episode of SmackDown! to earn a title shot. Two weeks later on November 7, they defeated Angle and Benoit in a two out of three falls match to win their first Tag Team Championship. They soon lost the tag titles to Los Guerreros in a Triple Threat Elimination match that also involved former champions Angle and Benoit at Survivor Series. Shortly after the loss, Mysterio and Edge disbanded as a tag team.
On the March 6, 2003, episode of SmackDown!, Mysterio defeated Tajiri and Jamie Noble in a Triple Threat match to earn a shot at the WWE Cruiserweight Championship. At WrestleMania XIX, he challenged the champion Matt Hardy for the title, but lost after Shannon Moore interfered. On the May 22 episode of SmackDown!, Mysterio defeated Shannon Moore and Crash Holly in a handicap elimination match to regain the number one contendership for the Cruiserweight title, and he defeated Hardy to win his first Cruiserweight Championship (his first reign in WWE and his first singles championship in the WWE) on the June 5 episode of SmackDown!. Mysterio's reign ended when he lost the title to Tajiri on the September 25 episode of SmackDown!. Three months later, on the January 1, 2004, episode of SmackDown!, Mysterio defeated Tajiri to win his second Cruiserweight Championship. After a successful title defense against Jamie Noble at the Royal Rumble, Mysterio lost the title to Chavo Guerrero at No Way Out in February. At WrestleMania XX, Mysterio took part in a Cruiserweight Open for the title, but Guerrero retained the title. On the June 17 episode of SmackDown!, he defeated Chavo Classic for a record-setting third Cruiserweight Championship reign. He successfully defended the title against Classic's son Chavo Guerrero at The Great American Bash. While Mysterio was Cruiserweight Champion, Spike Dudley turned heel after plowing Mysterio through a table and joined the other Dudleys before winning the Cruiserweight Title from Mysterio on the July 29 episode of SmackDown!. At Survivor Series, he participated in a fatal four-way match for the Cruiserweight Title involving the champion Dudley, Chavo Guerrero, and Billy Kidman. Mysterio lost when Dudley pinned Guerrero to retain.
After an unsuccessful attempt at regaining the Cruiserweight Title, Mysterio formed a tag team with Rob Van Dam, and went on to win the Tag Team Championship from Kenzo Suzuki and René Duprée on the December 9 episode of SmackDown!. They successfully defended the title against the former champions at Armageddon, before losing the title to the Basham Brothers on the January 13, 2005, episode of SmackDown! after Van Dam was injured.
Mysterio then teamed up with Eddie Guerrero to win the Tag Team Championship back from the Bashams at No Way Out. During this time Mysterio had a video camera, which was called the "619 cam", during his entrance he taped members of the audience with this. In a departure from traditional booking, the new champions did not defend their title at WrestleMania 21, but instead had a match against each other which Mysterio won. Two months later, at ECW One Night Stand, Mysterio faced and defeated long-time rival Psicosis for the first time in nearly five years.
The match at WrestleMania was part of a storyline in which Guerrero turned on Mysterio and beat him up after abandoning him during a match against MNM for the Tag Team Championship. Then after a no disqualification match against Chavo, Eddie came out and slammed Mysterio on the steel steps, displaying Eddie's increasing frustration with being unable to defeat Mysterio. Guerrero and Mysterio continued to feud, with Guerrero threatening to reveal a secret he and Mysterio shared involving Mysterio's real life son Dominick, unless Mysterio deferred to Guerrero's authority. Guerrero later revealed that, in the storyline, he was Dominick's biological father. The storyline went that Guerrero knew Mysterio was having trouble starting his own family, so Guerrero left Dominick as a baby with Mysterio and his wife Angie to raise. In subsequent weeks, Guerrero threatened to take custody of Dominick, drawing up custody papers and having his lawyer present them to Mysterio. At SummerSlam, Mysterio defeated Guerrero in a ladder match for the custody of Dominick. Their feud ended when Guerrero gained a victory over Mysterio in a steel cage match. On November 13, 2005, Eddie Guerrero was found dead in his hotel room in Minneapolis, Minnesota. That same day at a WWE "Super Show" where SmackDown! and Raw were both taped, Mysterio gave an emotional speech about Guerrero, and in a show of respect removed his mask (though he put his head down, so no one could see his face). Mysterio went on to defeat Shawn Michaels in an interpromotional match later that night. After the match, Michaels and Mysterio hugged in the ring and Mysterio pointed up to the sky, crying, in memory of Guerrero.
Mysterio participated in the main event of Survivor Series as part of Team SmackDown! along with Randy Orton, Bobby Lashley, Batista, and John "Bradshaw" Layfield who defeated Team Raw (Shawn Michaels, Kane, Big Show, Carlito, and Chris Masters). After Survivor Series, Mysterio started a feud with Big Show after Mysterio eliminated Big Show at Survivor Series, Mysterio would face Big Show in a match billed as "David vs. Goliath" in a SmackDown! special show, and ended as a "no contest" when Big Show's tag team partner Kane interfered in the match. Mysterio continued to feud with Raw's World Tag Team Champions, and found a tag team partner in World Heavyweight Champion Batista. They were booked to face Raw's Kane and Big Show in a tag match at Armageddon. Before Armageddon, Batista and Mysterio defeated MNM on the December 19 episode of SmackDown! to win the WWE Tag Team Championship in a match they both dedicated to Eddie Guerrero. Now the Tag Team Champions, Mysterio and Batista's match with Big Show and Kane was billed as "Champions vs. Champions." Mysterio and Batista lost the match when Kane pinned Mysterio after a chokeslam. On the December 30 episode of SmackDown!, MNM invoked their rematch clause, defeating Batista and Mysterio after interference from Mark Henry to regain the Tag Team Championship. The following week, Mysterio and Batista received their rematch for the titles in a steel cage match, which they lost after more interference by Henry. On the January 10, 2006, episode of SmackDown!, Mysterio was involved in a 20-man battle royal for the vacant World Heavyweight Championship, but was eliminated by Henry.
Mysterio was the second entrant in the 2006 Royal Rumble match. He won the match and earned a world title shot, last eliminating Randy Orton. He lasted 62 minutes, a Royal Rumble record at the time. Orton urged him to put the title shot at stake in a match at No Way Out. In the weeks preceding No Way Out, Orton made disparaging remarks about Eddie Guerrero. Orton won at No Way Out, earning Mysterio's title shot for the World Heavyweight Championship at WrestleMania 22. General Manager Theodore Long re-added Mysterio to the WrestleMania 22 title match however, making it a Triple Threat match between Orton, Mysterio, and then-champion, Kurt Angle. At WrestleMania 22, Mysterio pinned Orton to become the new World Heavyweight Champion. On the following episode of SmackDown!, Mysterio – who was billed as being an "underdog champion", made his first successful World Heavyweight title defense against Orton. Mysterio went on to retain his title again during a WrestleMania rematch on SmackDown! against Angle three weeks later.
Mysterio quickly moved into a feud with the United States Champion John "Bradshaw" Layfield. The rivalry kicked off after JBL, celebrating his U.S. Championship win, stated he deserved the World Heavyweight title. This feud saw Mysterio face off against three opponents chosen by JBL in the three weeks leading up to their title match at Judgment Day. Mysterio was defeated by Mark Henry and The Great Khali in separate non-title matches before wrestling Kane to a "no contest"; Mysterio retained his title against JBL at Judgment Day. The feud intensified when JBL lost the U.S. Title to Bobby Lashley five days later on SmackDown! after being tricked by Mysterio to take on all comers like Mysterio himself had. JBL vowed that if he did not win his rematch against Mysterio, he would quit SmackDown!. In their main event match, Mysterio retained the World Heavyweight Championship, causing JBL to leave SmackDown!, until ECW One Night Stand, when he announced his return as a color commentator. Mysterio was booked to defend against ECW wrestler Sabu at One Night Stand. In the weeks leading up to his title defense, Mysterio defeated Cruiserweight Champion Gregory Helms in a Champion vs. Champion match, and lost to Rob Van Dam at WWE vs. ECW Head-to-Head on June 7. At One Night Stand, Mysterio retained the title, after he and Sabu were ruled unable to continue following a triple jump DDT through a table by Sabu. Mysterio then retained his title in a match against Mark Henry, winning by disqualification after Chavo Guerrero handed Henry a chair and Mysterio acted as if he was hit, a tactic for which Eddie Guerrero was known.
Mysterio began a feud with King Booker after Booker won a battle royal to become the number one contender for the World Heavyweight Championship. Booker attacked Mysterio from behind backstage with the help of Booker's wife Queen Sharmell. The next week on SmackDown!, Mysterio gained revenge by attacking Booker and his "court". This rivalry continued for several weeks and saw Mysterio defeating Booker's court member William Regal on an episode of SmackDown!, moments before attacking the challenger and hitting him with a 619 around the steel post. On July 23 at The Great American Bash, Mysterio lost the World Heavyweight Championship to King Booker after Chavo interfered in the match and turned on Mysterio, hitting him with a steel chair. Guerrero cost Mysterio his rematch the following week. This culminated in a match at SummerSlam where Mysterio lost to Guerrero after Vickie Guerrero tried to stop both men from fighting, but accidentally knocked Mysterio off the top turnbuckle. Vickie then along with Chavo turned on Mysterio after she hit him in the back with a steel chair and gave him an injury, thus, siding with Guerrero. Mysterio then defeated Guerrero in a Falls Count Anywhere match at No Mercy. Subsequently, Guerrero challenged Mysterio to an "I quit" match for the October 20 edition of SmackDown. In that match, Chavo injured Mysterio's knee, using the match to write Mysterio out of the storyline for a while to get knee surgery.
Mysterio made his in-ring return at SummerSlam on August 26, 2007, defeating Guerrero, after Guerrero obsessed over Mysterio's return as well as wanting to injure Mysterio again. On the August 31 episode of SmackDown!, Mysterio won a "Championship Competition" to become the number one contender for the World Heavyweight Championship, defeating Batista and Finlay. On the September 7 episode of SmackDown!, Mysterio had an "I Quit" match with Guerrero, which he won after hitting Guerrero's knee with a steel chair repeatedly in a similar manner to which Mysterio had been put out of action, to end the feud. Mysterio then began a feud with The Great Khali, which led to a World Heavyweight Championship match at Unforgiven. The match was later made a Triple Threat match, also involving Batista, who won it.
Mysterio then began a feud with Finlay, an opponent chosen by JBL. The rivalry was marked as "Fight vs. Flight", contrasting the fighting styles of both wrestlers – Finlay's physicality, versus the high-flying Mysterio. On October 28, after fighting to a "no contest" at No Mercy, followed by a double-disqualification in a number one contender's match for Batista's World Heavyweight title on the next SmackDown! he defeated Finlay in a Stretcher match at Cyber Sunday. During this feud, he conceded one match to Finlay on an episode of SmackDown! and was part of the winning team at Survivor Series which consisted of both wrestlers on opposing sides (although Mysterio was second to be eliminated).
He re-entered the world title picture when he emerged victorious in the Beat the Clock challenge for the chance to face the World Heavyweight Champion Edge at the Royal Rumble. He was unsuccessful in winning the championship. WWE's official website announced on February 14 that Mysterio suffered a biceps injury during an overseas tour. Despite the injury, Mysterio faced Edge for the title again at No Way Out. On the February 22 episode of SmackDown!, Mysterio announced that his injury would keep him out of action for at least six months, and he eventually underwent three surgeries within the space of a month.
Mysterio made his return on the June 23, 2008, episode of Raw, as the first wrestler to be drafted in the 2008 WWE Draft from SmackDown to the Raw brand. Mysterio made his Raw in-ring debut on July 7, pinning Santino Marella after a 619. General Manager Mike Adamle announced that John Cena was injured and that Mysterio would replace him in the Championship Scramble at Unforgiven. The next week, Mysterio made his return to Raw after an extended absence by attacking Kane, turning back numerous claims that Kane had "ended his career". Mysterio then made his in-ring return at Unforgiven, competing in the Raw Championship scramble match. Mysterio put his mask on the line in a singles match at No Mercy, which he won by disqualification after Kane attacked him with a steel chair. He defeated Kane again at Cyber Sunday, this time in a No Holds Barred match, and again at Survivor Series, when the pair were on opposing sides in a five-on-five elimination match. Mysterio participated in the 2009 Royal Rumble match, entering first and spending 49 minutes and 24 seconds in the match, before being eliminated by Big Show. The following night on Raw, he qualified for the Elimination Chamber match for the World Heavyweight Championship at No Way Out, but was eliminated by Edge when the two were the last men in the Chamber match.
Later, John "Bradshaw" Layfield (JBL) accepted Mysterio's challenge for Layfield's Intercontinental Championship at WrestleMania XXV, which Mysterio won in 21 seconds. His win made Mysterio the twenty-first Triple Crown Champion in WWE history. Mysterio was drafted back to SmackDown! during the 2009 WWE Draft on the April 13 episode of Raw, in the process making the Intercontinental Title exclusive to SmackDown for the first time since mid-2002. He then began an extended feud with Chris Jericho, successfully defending his title at Judgment Day. At Extreme Rules, Jericho managed to unmask Mysterio and pin him for the Intercontinental Championship; while Mysterio managed to cover his face after being unmasked, Jericho took the opportunity to roll him up and win the title. As a result, Mysterio and Jericho were booked in a Title vs. Mask match at The Bash, Mysterio emerged from the acclaimed match victorious after tricking Jericho with a second mask. He then moved into a feud with Dolph Ziggler, defeating him at both Night of Champions and SummerSlam. On August 2, WWE announced that Mysterio would be suspended for 30 days, effective September 2, for violating the company's Wellness Policy. On the September 4 episode of SmackDown (taped on September 1), Mysterio lost the Intercontinental Championship to John Morrison.
Mysterio returned from his suspension at Hell in a Cell, teaming with former tag team partner Batista to face Jeri-Show (Chris Jericho and Big Show) for the Unified Tag Team Championship. They failed to win the titles, as Mysterio was KO punched and pinned by Big Show. At Bragging Rights, Mysterio was unsuccessful in winning the World Heavyweight Championship in a Fatal Four-Way match involving Batista, CM Punk, and then-champion The Undertaker. During the match, Mysterio broke up Batista's pin on Undertaker possibly costing him the match and the title. After the match, Batista turned heel and attacked him. Mysterio faced Batista at Survivor Series, where he lost by referee stoppage after Batista performed three Batista Bombs on him. Mysterio was defeated by Batista again in a street fight on the December 11 episode of SmackDown. A few weeks later Mysterio defeated Batista and was named the number one contender for the World Heavyweight Championship, but his title match against The Undertaker ended in a no contest after Batista interfered. On January 1, 2010, Mysterio participated in a Beat the Clock Tournament for a World Heavyweight Championship match at the Royal Rumble. In the tournament, he defeated his former rival Chris Jericho in the quickest time, and prevented Batista from beating it by interfering in his match. This led to a number one contender's match between the duo the following week, which also ended in a no contest following interference from the Undertaker. The following week in a re-match, Mysterio defeated Batista in a Steel Cage match, but failed to win the championship at the Royal Rumble.
Following the Rumble, Mysterio qualified for an Elimination Chamber match for the World Heavyweight Championship at the Elimination Chamber pay-per-view. In the weeks preceding the event, Mysterio began a feud with CM Punk that also involved Punk's Straight Edge Society. During the Elimination Chamber match, Mysterio eliminated Punk, but was ultimately eliminated by John Morrison. Mysterio continued to feud with Punk, costing him a Money in the Bank qualifying match and defeating SES member Luke Gallows. During the on-screen celebration of Mysterio's daughter's ninth birthday, Punk interrupted, taunting Mysterio and challenging him to a match at WrestleMania XXVI, which Mysterio later accepted. Punk later added the stipulation that if Mysterio were to lose at WrestleMania, he would be forced to join the SES. However Mysterio defeated Punk at WrestleMania. Five days later on SmackDown, Punk challenged Mysterio to another match at Extreme Rules, with the stipulation that if Mysterio won, Punk would have his head shaved. At Extreme Rules, Mysterio lost to Punk. At Over the Limit, Mysterio faced CM Punk again with both previous stipulations in place (Mysterio's allegiance to The SES vs Punk's hair.) Mysterio defeated Punk after Kane interfered, resulting in Punk's hair being shaved.
On the May 28 episode of SmackDown, Mysterio unsuccessfully fought The Undertaker to qualify for the World Heavyweight Championship title match at Fatal 4-Way. The Undertaker suffered a legitimate injury during the match, and a storyline was introduced to explain his absence on television, stating he had been found in a vegetative state by his brother Kane. On June 4, Mysterio won a Battle Royal to earn The Undertaker's place at Fatal 4-Way by last eliminating Kane, and went on to win the World Heavyweight Championship for the second time. At Money in the Bank, Mysterio defeated Jack Swagger to retain the World title, however, Swagger attacked him after the match. Kane, who had won his Money in the Bank ladder match earlier that night, cashed in for a title shot and quickly defeated Mysterio to win the World Heavyweight Championship after it had appeared that he was saving Mysterio from Swagger's attack. Kane later blamed Mysterio for The Undertaker's fictional injuries. On the July 20 episode of SmackDown, Mysterio defeated Swagger in a two out of three falls match to remain the number one contender for the World Heavyweight Championship, earning a title match against Kane at SummerSlam. Kane defeated Mysterio at SummerSlam with a seemingly commemorative Tombstone Piledriver, but the Undertaker returned to exonerate Mysterio and blame Kane.
Five days later on the August 20 episode of SmackDown, Mysterio lost to the debuting Alberto Del Rio by submission. Del Rio, however, continued his attack after the match, sidelining Mysterio for a month, in which time Del Rio would taunt him. The following week a feud was sparked between the two, when Del Rio attacked him following a match with Kane. On the October 8 episode of SmackDown, Mysterio defeated Del Rio, and thus ending his undefeated streak. At Bragging Rights, Mysterio represented Team SmackDown, and despite being attacked by teammate Del Rio, he and Edge managed to defeat the rest of Team Raw, giving Team SmackDown the victory. At Survivor Series, Mysterio led a team to victory over Team Del Rio, and at Tables, Ladders & Chairs, both were part of a fatal four-way match for the World Heavyweight Championship, won by Edge. His feud with Del Rio culminated on the January 7, 2011, episode of SmackDown in a two out of three falls match, which Del Rio won by countout.
On the January 21 episode of SmackDown, Mysterio defeated Cody Rhodes. During the match, he broke Rhodes' nose when he hit Rhodes with a 619 with his exposed knee brace, thus sparking a feud. Mysterio participated in the Royal Rumble match at the Royal Rumble, though he was eliminated by Wade Barrett. Five days later on SmackDown, Mysterio qualified for a spot in the Elimination Chamber match at the Elimination Chamber pay-per-view for the World Heavyweight Championship by defeating Jack Swagger. At the event he made it to the final two but was eliminated by Edge. On the February 25 episode of SmackDown, Mysterio was tricked and attacked by Cody Rhodes and his father, Dusty Rhodes, resulting in Mysterio being unmasked by Rhodes. At WrestleMania XXVII, Mysterio was defeated by Rhodes in a singles match. Mysterio defeated Rhodes in a rematch on the April 23 episode of SmackDown and at Extreme Rules in a Falls Count Anywhere match to end the feud.
In the 2011 WWE Draft, Mysterio was drafted back to Raw. On the May 9 episode of Raw, Mysterio lost a triple threat match to determine the number one contender for the WWE Championship. Following the match, Mysterio was attacked by R-Truth, which led to a match between the two at Over the Limit, which R-Truth won. In May, Mysterio started feuding with CM Punk, with the pair exchanging victories on consecutive episodes of Raw. The feud culminated in a singles match on June 19 at WWE Capitol Punishment, where Punk emerged victorious. On July 17 at Money in the Bank, Mysterio failed to capture the Raw Money in the Bank briefcase, as the match was won by old rival Alberto Del Rio. The following night on Raw, Mysterio took part in a tournament for the vacant WWE Championship and advanced to the finals. On July 25, Mysterio defeated The Miz in the final to win his first WWE Championship, but he lost the title to John Cena later that night. On August 15, Mysterio received a rematch for the WWE Championship against new champion Alberto Del Rio, but lost via submission. Mysterio suffered an injury in late August 2011, and a storyline was put in place to write Mysterio off television, by blaming Alberto Del Rio. Mysterio returned at the Slammy Awards to present the Superstar of the Year Award to CM Punk.
On April 26, 2012, WWE reported that Mysterio had been suspended for 60 days due to his second violation of the company's Talent Wellness Program policy and that his suspension would expire on June 25.
After an absence of almost a year, Mysterio returned on the July 16 episode of Raw, saving Zack Ryder from his old rival, Alberto Del Rio. On August 19 at SummerSlam, Mysterio unsuccessfully challenged The Miz for the Intercontinental Championship. During the match, Mysterio suffered a legitimate concussion, rendering him inactive for a week, but he returned to SmackDown on the August 31 episode. On September 16 at Night of Champions, Mysterio failed again to capture the Intercontinental Championship from The Miz in a fatal four-way match, also involving Cody Rhodes and Sin Cara. The following night on Raw, Mysterio and Sin Cara teamed up to defeat Primo and Epico in a tag team match, after which they were attacked by The Prime Time Players (Darren Young and Titus O'Neil). According to Mysterio, he took the decision to leave WWE when he saw no creative direction about his tag team with Sin Cara. In October, Mysterio and Sin Cara entered a tournament to determine the number one contenders to the WWE Tag Team Championship, defeating Primo and Epico in the first round and the Prime Time Players in the semi-finals. Mysterio and Sin Cara were set to face the team of Cody Rhodes and Damien Sandow on the October 15 episode of Raw, but the match was postponed due to Mysterio legitimately suffering from effects of the stomach flu. The final took place the following week, on October 22, where he and Sin Cara were defeated by Rhodes and Sandow. On November 18 at the Survivor Series pay-per-view, Mysterio and Sin Cara were victorious in a 10-man elimination tag team match alongside Brodus Clay, Justin Gabriel, and Tyson Kidd against Primo, Epico, the Prime Time Players, and Tensai. On December 16 at TLC: Tables, Ladders & Chairs, Mysterio and Sin Cara were defeated by Team Rhodes Scholars (Cody Rhodes and Damien Sandow) in a number one contenders Table match for the WWE Tag Team Championship. Two days later on SmackDown, Mysterio was sidelined with a storyline injury when he and Sin Cara were attacked by The Shield. This was used to write them off television, as Mysterio was taking some time off, and Sin Cara underwent a knee surgery. Mysterio returned on January 27, 2013, at the Royal Rumble, entering the Royal Rumble at number fourteen but was eliminated by Wade Barrett. In March, Mysterio took another leave of absence due to a legitimate knee injury, explained in storyline as an attack by Mark Henry.
After eight months, Mysterio returned at a WWE live event on October 17, 2013, and returned to television as part of the Spanish commentary team at Hell in a Cell. On the November 18 episode of Raw, Mysterio saved CM Punk and Daniel Bryan from an attack by The Wyatt Family and The Real Americans (Jack Swagger and Antonio Cesaro), which led to Mysterio being part of a 10-man elimination tag team match at Survivor Series in which Mysterio's team lost after he was eliminated by sole survivor Roman Reigns. At TLC: Tables, Ladders and Chairs, Mysterio teamed with Big Show to unsuccessfully challenge Cody Rhodes and Goldust for the WWE Tag Team Championship in a fatal four-way match also involving RybAxel (Ryback and Curtis Axel) and The Real Americans. At the Royal Rumble pay-per-view on January 26, 2014, Mysterio entered the Royal Rumble match at #30, but was eliminated by Seth Rollins. At WrestleMania XXX, Mysterio competed in the André the Giant Memorial Battle Royal but was eliminated by Cesaro. His last appearance in WWE was on the April 7 episode of Raw, where Mysterio lost to a returning Bad News Barrett and subsequently decided to take time off to heal a wrist injury.
On February 26, 2015, WWE officially announced that Mysterio's WWE contract had expired, ending his nearly 13-year tenure with the company.
On January 28, 2018, at the Royal Rumble, Mysterio was a surprise entrant in the men's Rumble match as part of a one-time deal with WWE. He entered at number 27, eliminating Adam Cole before later being eliminated by Finn Bálor. On April 27, Mysterio participated in the 50-man Royal Rumble match at the Greatest Royal Rumble event. He entered at number 28, eliminating Luke Gallows but was eliminated by Baron Corbin. On June 26, Mysterio was revealed as one of the pre-order bonus character for WWE 2K19. On September 19, it was confirmed Mysterio had signed a two-year contract with WWE.
On October 16 as part of SmackDown 1000, Mysterio competed in his first singles match with the company since April 2014. He defeated United States Champion Shinsuke Nakamura to qualify for the WWE World Cup. During the World Cup at the Crown Jewel event, Mysterio defeated Randy Orton in the first round, but was attacked by Orton after the match. Later in the night, Mysterio lost to The Miz in the semi-finals. On the November 6 episode of SmackDown Live, Mysterio defeated Andrade "Cien" Almas to qualify for Team SmackDown in a 5-on-5 Survivor Series elimination match at Survivor Series. The following week, team co-captain The Miz suggested that Mysterio be removed from the team. His suggestion stemmed from Mysterio defeating him on SmackDown Live a few weeks prior. Mysterio faced The Miz that night, defeating him to remain on the team. At the event, Mysterio eliminated Finn Bálor before being eliminated by Braun Strowman, and Team SmackDown ultimately lost to Team Raw. Two nights later on SmackDown Live, Mysterio lost to Randy Orton. After the match, Orton attacked Mysterio with a chair, as well as ripped Mysterio's mask off of his face. The two fought the following week, with Orton getting the upper-hand. At TLC: Tables, Ladders & Chairs, Mysterio defeated Orton in a Chairs match. Mysterio entered the Royal Rumble match at #25 at the namesake event but was eliminated by Orton. Mysterio failed to win the United States Championship at Fastlane in a fatal-4-way where Samoa Joe retained in a match also involving R-Truth and Andrade. On the March 12 edition of SmackDown Live, Mysterio pinned Joe in a tag team match which led to Mysterio earning a United States Championship opportunity against Joe at WrestleMania 35 where he was defeated by Joe. During the 2019 WWE Superstar Shake-up, Mysterio was drafted to Raw. At Money in the Bank on May 19, Mysterio defeated Joe to win his first United States Championship, becoming the twenty-first WWE Grand Slam Champion in the process. Two weeks later on Raw, Mysterio announced that he would vacate the title the week after due to suffering an injury from a post-match beatdown by Joe.
Mysterio returned on 8th July's edition of Raw and issued an open challenge which was accepted by Bobby Lashley where he was defeated by him and also suffered a post-match assualt from Lashley. In August, Mysterio teased his retirement due to multiple losses and amounting injuries, with his son trying to persuade him to not give up. On the 30 September edition of Raw, Mysterio was meant to take on Seth Rollins in a match for the Universal Championship, which he earned recently by winning a multi-man match. However, he was greeted by Brock Lesnar and Paul Heyman, and Lesnar attacked Mysterio. Lesnar then beat up Rey's son Dominick who was in the front row, resulting in a storyline injury for the latter. On the following SmackDown, Mysterio assisted the debut of Cain Velasquez to attack Lesnar after his WWE Championship win. After defeating Velasquez at Crown Jewel, Lesnar was attacked by Mysterio with a steel chair. This led to Lesnar quitting the SmackDown brand on the November 1 episode of SmackDown so he could challenge Raw superstar Mysterio. On the November 4 episode of Raw, after causing destruction in his attempt to find Mysterio, Mysterio blindsided Lesnar and attacked him with a steel pipe. Mysterio vowed he would gain revenge for Lesnar's attacks on his son Dominick and would take the only thing Lesnar cares about at, the WWE Championship, at Survivor Series. At the event, Mysterio lost to Lesnar despite interference from his son Dominick.
On the November 25 episode of Raw, Mysterio defeated Randy Orton, Drew McIntyre and Ricochet in a fatal four-way match to become the number one contender for the United States Championship, earning him an immediate title match with United States Champion AJ Styles. After The O.C. were sent backstage by the referee for interfering in the match, when the referee was stunned by Styles recoiling from a 619 by Mysterio, The O.C. returned to attack Mysterio, only to be overpowered by Orton, who then helped Mysterio take down Styles with a second 619 and an RKO before subsequently pinning Styles to capture his second US title. At a live event at Madison Square Garden on December 26, Mysterio lost the title to Andrade. He then attempted to win the title back on the first Raw of 2020 on January 6, but due to interference by Zelina Vega, Andrade pinned Mysterio to retain the title.
On the April 20 edition of Raw, Mysterio pinned Murphy to qualify for the Money in the Bank ladder match. At the event, Mysterio lost. During the match, he and Aleister Black were "thrown off the roof" of the WWE headquarters by King Corbin. The next night on Raw, Mysterio was savagely attacked by Seth Rollins in a tag team match, where he and Black battled Rollins and Murphy, and won by disqualification when Rollins pulled Mysterio off of the ring apron. In the midst of the post match assault, Mysterio's eye was severely injured when Rollins forced his face onto the steel steps due to his frustration at not being able to defeat Drew McIntyre the previous night. This resulted in speculation that Mysterio would "retire", following weeks of being mocked by Rollins. However, Mysterio and Dominic later began targeting Rollins, with Mysterio challenging Rollins to an Eye for an Eye match at The Horror Show at Extreme Rules, where the match could only be won by "removing" an opponent's eyeball. At the event, Mysterio lost the match in a gruesome manner, after Rollins successfully "detached" his eye from its socket.
As part of the 2020 draft in October, Mysterio was drafted to the SmackDown brand. Rey Mysterio and his son Dominik would continue feuding with Seth Rollins and Murphy on SmackDown. Over time, Murphy would show signs of turning on Rollins and wanting to be a part of the Mysterio family, but Rey was hesitant and wouldn't allow Murphy to join them. Rollins and Mysterio would eventually face each other in a No Holds Barred 'Final Chapter' match on the November 13 episode of SmackDown, where Mysterio would pick up the win and accept Murphy as part of the Mysterio family.
At Survivor Series, Rey and Dominik would both compete in a dual-brand battle royal, but both men were eliminated. On the December 4 episode of SmackDown, Mysterio would team with Big E and Daniel Bryan to defeat Shinsuke Nakamura, Robert Roode and Dolph Ziggler. At Tribute to the Troops, Mysterio would team with The Street Profits, Daniel Bryan and Jeff Hardy to defeat Elias, King Corbin, Sami Zayn, Dolph Ziggler and Robert Roode.
On the January 8, 2021 episode of SmackDown, Mysterio would compete in a gauntlet match to determine Roman Reigns' opponent at the Royal Rumble. Mysterio would eliminate Sami Zayn but would be eliminated by the next participant, Shinsuke Nakamura. On the January 15 episode of SmackDown, Mysterio would face King Corbin in a losing effort. Mysterio would enter the Royal Rumble match at number twenty-six, but would be eliminated by AJ Styles' bodyguard, Omos. On the February 19 episode of SmackDown, Rey and Dominik would team up to face Otis and Chad Gable and would win via disqualification. On the following week's episode of SmackDown, Otis and Chad Gable would defeat Rey and Dominik. On the March 19 episode of SmackDown, Rey and Dominik Mysterio would defeat The Street Profits. On the March 26 episode of SmackDown, Rey would defeat Dolph Ziggler. On the April 2 episode of SmackDown, Rey, Dominik and The Street Profits would be defeated by Dolph Ziggler, Robert Roode, Otis and Chad Gable. On the WrestleMania edition of SmackDown, Rey and Dominik Mysterio would face Dolph Ziggler and Robert Roode, The Street Profits, and Otis and Chad Gable for the SmackDown Tag Team Championships, but were unsuccessful as Roode and Ziggler would retain their titles. On the April 16 episode of SmackDown, Mysterio would defeat Otis. At WrestleMania Backlash, Rey and Dominik Mysterio defeated Dolph Ziggler and Robert Roode to win the SmackDown Tag Team Championships and in the process, they also became the first ever father-son tag team champions in WWE history.
On the June 4 episode of SmackDown, the Mysterios successfully defended their titles against The Usos, albeit with controversy as Jimmy's shoulder was lifted although the referee wasn't aware. After Adam Pearce and Sonya Deville granted a rematch later that same night, the Mysterios again retained their titles after Roman Reigns interfered and attacked the Mysterios, causing a disqualification, and both were assaulted by Reigns afterwards. The following week on SmackDown, Rey called out Reigns for attacking Dominik, and challenged Reigns to a Hell in a Cell match at the namesake pay-per-view, but before Reigns could answer, Rey attacked Reigns with a kendo stick, but was ultimately overpowered, and while Dominik joined the brawl, Reigns powerbombed Dominik over the top rope and out of the ring. The next day on Talking Smack, Paul Heyman, Reigns' "special council", formally accepted Rey's challenge on Reigns' behalf. On June 17, however, it was announced that the match would instead take place on the June 18 episode of SmackDown, marking the first Hell in a Cell match to take place on SmackDown in which he lost to Reigns. At Money in the Bank, The Mysterios lost the titles to The Usos, ending their title reign at 63 days. At SummerSlam, The Mysterios would be defeated by The Usos in a rematch for the SmackDown Tag Team Championships. As part of the 2021 Draft, both Rey and Dominik were drafted to the Raw brand. In October, Mysterio entered the King of the Ring tournament, where he lost to Sami Zayn in the first round.
Mysterio later lost to Seth Rollins in a ladder match in a contest which also featured Kevin Owens and Finn Bálor to determine the number one contender for the WWE Championship. Mysterio was later named as a member for Team Raw for the traditional Survivor Series showdown with Team SmackDown, but was replaced by Austin Theory before the event took place. On the December 20 episode of Raw, Rey and Dominik defeated the team of AJ Styles and Omos. In January, Mysterio was unveiled as the cover star of WWE 2K22. On the January 17 edition of Raw, he was announced as a participant of the 2022 Royal Rumble match, and later that night teamed with Dominik and The Street Profits to defeat Dolph Ziggler, Robert Roode, Apollo Crews and Commander Azeez. At the Royal Rumble, Mysterio entered the match at number twenty-three, eliminating Dolph Ziggler before being eliminated himself courtesy of Otis.
Following the Royal Rumble, Rey and Dominik entered into a feud with The Miz. At Elimination Chamber, Mysterio defeated the Miz via pinfall. The next night on Raw, The Miz challenged Rey and Dominik to a tag team match at WrestleMania 38, revealing his tag team partner to be Logan Paul. At the event, the Mysterios lost to The Miz and Paul. Rey and Dominik then entered into a short feud with the debuting Veer Mahaan. Following several attacks from the latter, including Dominik being written off WWE television for several weeks, Mahaan defeated Mysterio on the June 13 episode of Raw. Following this, the Mysterio's later feuded with the newly formed stable The Judgment Day. Finn Balor and Damian Priest would continually attempt to have Dominik join the stable and betray Rey, but Dominik repeatedly deflected the duo's attempts at having him turn on Rey. At Clash at the Castle on September 3, Rey and Edge defeated Bálor and Priest, and after the match, Dominik hit Edge with a low blow and hit a clothesline on Rey, turning heel and disbanding the Mysterios. On the October 14 episode of SmackDown, he was transferred to the blue brand. On Thanksgiving, Rey was attacked by Dominik and Rhea Ripley after Rey refused to let them into the house. On Christmas Eve, Dominik and Ripley visited Rey's parent's home. A confrontation ensued between Dominik, Ripley, Rey and Angie (Rey's wife and Dominik's mother) outside of the house with Dominik shoving Rey and Angie slapping Ripley. At the Royal Rumble on January 28, 2023, Mysterio was scheduled to enter the Royal Rumble match at number seventeen, but was unable to compete due to being attacked by his son, Dominik, who entered the match at number eighteen.
On March 10, WWE announced that Mysterio would be inducted into the WWE Hall of Fame as a part of the class of 2023. On the March 24 episode of SmackDown, with the Mysterio family in attendance, Mysterio would lose to LA Knight due to Dominik interfering. Dominik would then go up to the Mysterio family and antagonize them, resulting in Rey finally hitting Dominik, where a match between Rey and Dominik at WrestleMania 39 would be made official. On the March 31 episode of SmackDown, before he would be inducted into the WWE Hall of Fame later that day, Rey would reform the Latino World Order by gifting LWO shirts to Legado Del Fantasma (Santos Escobar, Zelina Vega, Joaquin Wilde, and Cruz Del Toro) as the group had aided Mysterio against The Judgment Day for several weeks prior. Rey would go on to defeat Dominik on night one of the event thanks to the help of Bad Bunny. On the August 11 episode of SmackDown, Mysterio defeated Austin Theory to capture his third WWE United States Championship after replacing LWO stablemate Santos Escobar due to injury. In a rematch, Mysterio successfully defended his title against Theory at Payback. On the September 29 episode of SmackDown, Mysterio faced off against Santos Escobar for the United States Championship, where Mysterio emerged victorious. After the match, Bobby Lashley and the Street Profits attacked them both. On SmackDown LowDown, it was announced that the LWO would take on Lashley and the Profits in a six-man tag-team match at Fastlane. On the October 6 episode of SmackDown, during a match between Lashley and Mysterio, the Street Profits would attack Cruz Del Toro and Joaquin Wilde, making them ineligible to compete at Fastlane. At the event, Carlito would return to team up with Mysterio and Escobar, winning the tag match for the LWO. On the October 20 episode of SmackDown, Logan Paul returned to WWE and challenged Mysterio to a United States Championship match at Crown Jewel, which Mysterio accepted. At the event on November 4, Mysterio lost the title after Paul used brass knuckles, ending his third reign at 85 days. On the following episode of SmackDown, Carlito blamed Escobar for Mysterio losing the title, saying he intentionally left the brass knuckles in the ring for Paul to use against Mysterio. Later that night, after Carlito lost to Lashley, Escobar attacked Mysterio as he was checking on Carlito. It was later revealed that Mysterio had underwent surgery for his injured knee and would be out of action for at least six weeks.
After a three-month hiatus, Mysterio returned on the March 1 episode of SmackDown, assisting Carlito in winning a street fight against Escobar. Three weeks later, Rey was defeated by Escobar after interference from Dominik. The following week, Mysterio introduced Dragon Lee as the newest member of the LWO, and the duo subsequently challenged Escobar and Dominik to a tag team match at WrestleMania XL, which was made official for night one. The following week, however, Lee was attacked backstage, rendering him unable to compete at WrestleMania. Rey was assisted by Andrade to fend off Escobar and Dominik. At WrestleMania XL, Mysterio and Andrade defeated Escobar and Dominik after interference from Lane Johnson and Jason Kelce. On the April 26 episode of SmackDown, Rey and Lee defeated Los Lotharios (Angel and Berto) in a tag team match. After the match, Escobar revealed that Carlito had attacked Lee. Carlito then proceeded to attack both Lee and Mysterio after Escobar's revelation. On night two of the 2024 WWE Draft, Mysterio and the rest of the LWO were drafted to the Raw brand.