Guerrero joined World Championship Wrestling (WCW) in May 1996. He made his in-ring debut wrestling Steven Regal in a dark match. On July 22—Guerrero's WCW Monday Nitro debut—he lost to Dean Malenko via submission. On August 3, 1996, Guerrero received his first title shot in WCW against Ric Flair on WCW Saturday Night for the WCW United States Championship. Flair beat Guerrero via submission to retain his championship.
Guerrero's first pay-per-view appearance was in a dark match loss to Konnan at Hog Wild. Then at WCW WorldWide, on August 11, 1996, he and Eddie Guerrero defeated High Voltage. After a series of singles wins, Guerrero faced Diamond Dallas Page after a short feud at Fall Brawl in a losing effort on September 15.
While in WCW, Guerrero shared the limelight with his uncle Eddie, becoming a reluctant ally of his uncle's. As part of their storyline, Eddie continually tried to make Guerrero adopt Eddie's cheating tactics, but he often refused to do so. Eventually, Guerrero's treatment at the hands of Eddie would drive him "crazy," and he adopted the gimmick of a psycho fixated with a hobby horse he dubbed "Pepé." This led to a feud with Norman Smiley in which Pepé was thrown into a woodchipper. Another result of his insanity was his inability to join Eddie's Latino World Order stable, which was a take-off of the nWo. On June 14, 1998, Guerrero defeated his uncle Eddie at The Great American Bash. In July 1998, at the Bash at the Beach, Guerrero faced Stevie Ray in a "tune up match" before he faced Eddie in a Hair versus Hair match, a match where the winner gets to shave his opponent's hair. Guerrero lost and began to shave his own hair off.
On January 17, 1999, at Souled Out, Guerrero was defeated by Norman Smiley in a match that was booked due to Guerrero's companion Pepe being burnt by Smiley, ending the Pepe gimmick.
Guerrero and Billy Kidman teamed together for a WCW Tag Team Championship tournament held on Nitro. Guerrero then turned on Kidman after being eliminated from the tournament, starting a feud. Guerrero faced Kidman for the WCW Cruiserweight Championship at WCW SuperBrawl IX on February 21, 1999, but failed to win the championship.
He was also a member of the comedy stable The Misfits in Action (MIA), consisting of himself, Hugh Morrus, Lash LeRoux and Van Hammer. They were managed by Major Gunns. Guerrero was billed as "Lieutenant Loco." As Loco, he defeated Daffney for the Cruiserweight Championship in a triangle match also involving Disco Inferno on the June 7, 2000 episode of Thunder. On June 11, 2000 at The Great American Bash, Lt. Loco defeated Disco Inferno to retain the title. Loco lost the championship to Lance Storm a month later on Nitro. At WCW Mayhem, Loco left the MIA and reverted to Chavo Guerrero Jr..
Guerrero won the Cruiserweight Championship from Mike Sanders on December 6 episode of Thunder. He retained the title against Rey Mysterio Jr. on February 18, 2001, at WCW SuperBrawl Revenge. As Cruiserweight Champion, Guerrero engaged in a feud against "Sugar" Shane Helms, eventually losing the championship to Helms at WCW Greed.
Guerrero's contract with WCW was one of the twenty-five contracts that were included in WCW's sale to the World Wrestling Federation (WWF). Like most of the wrestling talent that came over with WCW, Guerrero wrestled as a heel under the WCW banner as his WWF debut was as part of The Alliance, a group of WCW and ECW employees who had, in storyline, invaded WWF after their promotion was bought out. On April 13, 2002, Guerrero faced Billy Kidman on an episode of WWF Metal for the Cruiserweight Championship and lost the match via pinfall. Guerrero spent time as an undercard wrestler in the company, which was soon rebranded World Wrestling Entertainment, wrestling for the Cruiserweight Championship on numerous occasions.
Soon after returning to the active roster, Guerrero was aligned with his uncle Eddie, forming the tag team Los Guerreros. In contrast to his previous WCW storyline with his uncle, Guerrero fully adopted his uncle's policy of "Lie, Cheat and Steal" to win matches as part of the gimmick. Los Guerreros won the WWE Tag Team Championships at Survivor Series, when they defeated Kurt Angle and Chris Benoit and Edge and Rey Mysterio in a triple threat tag team elimination match. The duo turned face due to their popularity. On the February 6, 2003 episode of SmackDown!, Los Guerreros lost their tag team championships to Team Angle. At WrestleMania XIX, they were again defeated by Team Angle in a triple threat match for the tag team titles, also involving the team of Benoit and Rhyno. They continued to feud with Team Angle and won the championships back on the September 18 episode of SmackDown!. One month later, they lost the titles to The Basham Brothers. After losing their tag team championships, Guerrero became jealous of his uncle's growing popularity and WWE Championship ambitions, turned on Eddie, broke from the team, and turned heel again. He was soon joined by his father Chavo Classic, who sided with his son instead of his brother. Guerrero and his father teamed together to defeat Eddie and Kurt Angle on January 22, 2004 episode of SmackDown!. Eddie, however, defeated Guerrero at the 2004 Royal Rumble to end their feud.
At No Way Out, Guerrero defeated Rey Mysterio to win the WWE Cruiserweight Championship, following interference from his father. At WrestleMania XX, Guerrero successfully defended his title in a 10-man Cruiserweight Open by last eliminating Mysterio. In the following weeks, Guerrero defeated Mysterio, Funaki, Ultimo Dragon, Spike Dudley, Jamie Noble, and Nunzio in one-on-one title matches. On the May 6 episode of SmackDown!, Guerrero issued an open challenge for anyone he had not yet defeated him to face him for his title. The challenge was answered by Jacqueline, who defeated Guerrero for the title after she gave him a "low blow." He regained the title at Judgment Day. Guerrero then dropped the title on the May 20 episode of SmackDown! to his father, who "accidentally" pinned his son in a triple threat match which also involved Spike Dudley. Rey Mysterio later regained the title, and he and Chavo faced each other at The Great American Bash, however, Mysterio won the match.
On the August 26 episode of SmackDown!, Guerrero suffered a legitimate concussion due to Billy Kidman's shooting star press and had to be taken to the hospital. Guerrero returned as a face two months later, exacting revenge from Kidman, who had turned heel as a result of the injury to Guerrero. Shortly after his feud with Kidman ended, Guerrero returned to his heel persona. Guerrero went on to win the Cruiserweight Championship once again at No Way Out, after eliminating Paul London in a six-way cruiserweight gauntlet match. He lost the title to London in a battle royal a few weeks later; Guerrero was the first person eliminated from the battle royal when everyone else in the match ganged up to throw him out right at the beginning.
In June, Guerrero became one of the last minute trades in the 2005 WWE Draft, which saw him jump from SmackDown! to the Raw brand. The next week, on Raw, he denounced his Hispanic heritage in favor of the "Anglo-American way". This came after two weeks of being battered by the Mexican faction, The Mexicools. It led to the changing of his persona to "Kerwin White", a stereotypical, middle-class, white, conservative, Anglo-American man. He dyed his hair blond and often drove a golf cart to the ring which held his golf clubs. Soon after his debut, White started making suggestive remarks towards African Americans, Hispanics, Asian Americans, Native Americans, and other non-White people, specifically directed towards Shelton Benjamin. On an episode of Raw, White cost Benjamin a match against Rob Conway. Benjamin defeated White by disqualification the following week when White attacked him with his golf club. At Unforgiven, White was defeated by Benjamin. White then hired Nick Nemeth as his new "caddy" to help him in his matches.
On the morning of November 13, 2005, Guerrero's uncle Eddie tragically passed away. These events resulted in Guerrero dropping the Kerwin White gimmick and wrestling under his real name Chavo Guerrero again, as a face. He defeated John "Bradshaw" Layfield (JBL) on the November 18, 2005 episode of SmackDown!, using the "Three Amigos" triple suplexes and the Frog Splash in tribute to Eddie. He also used the cheating tactic which Eddie made famous: throwing a steel chair to an opponent who catches it (while he himself lies down, pretending to have been hit), so that the referee turns around and disqualifies the opponent.
On the February 24, 2006 episode of SmackDown!, Guerrero attacked Randy Orton when Orton began to insult Eddie and the heritage of the Guerreros. Guerrero was soon dragged out by security. On the February 27 episode of Raw, Guerrero faced off against Shelton Benjamin in a qualifying match for the Money in the Bank ladder match at WrestleMania 22. During the match, Orton interfered and hit Guerrero with the RKO, allowing Benjamin to get the pinfall victory. He proceeded to unsuccessfully challenge Benjamin for the WWE Intercontinental Championship on the April 3 episode of Raw.
Guerrero appeared at Judgment Day to support Rey Mysterio. At the Great American Bash, Guerrero interfered in Mysterio's World Heavyweight Championship match, ostensibly to help Mysterio. Guerrero turned heel once again, however, by hitting Mysterio with a steel chair, which allowed challenger King Booker to win the match and the title. On the August 4 episode of SmackDown!, Guerrero accused Mysterio of using Eddie's name to succeed, claiming that he had disrespected Eddie's memory. Guerrero went on to beat Mysterio at SummerSlam after Vickie Guerrero (Eddie's widow) accidentally knocked Mysterio off the top turnbuckle. On August 25, Vickie came down to the ring to apologize to Mysterio and Guerrero but turned on Mysterio by hitting him in the back with a steel chair. The following week on SmackDown!, Vickie announced herself as Guerrero's new manager. Mysterio gained his revenge on Guerrero by defeating him in a Falls Count Anywhere match at No Mercy. Guerrero eventually challenged Mysterio to an "I Quit" match, which Guerrero won, and as per the condition of the match, Mysterio was forced to leave SmackDown!.
A week later, Chris Benoit, another old friend of Eddie's, began feuding with Guerrero and Vickie, and the men would have numerous confrontations over the following weeks. Benoit defeated Guerrero to retain the WWE United States Championship at Survivor Series. After weeks of continued interaction, the two faced off in a United States title rematch at Armageddon that Guerrero lost when he tapped out to a Sharpshooter. Guerrero got yet another rematch the following Friday, losing the match after Vickie hit Benoit with the title belt. Guerrero snapped after the match, knocking over Vickie and attacking Benoit. The feud concluded with Benoit forcing Guerrero to submit in a no disqualification match.
At No Way Out, Guerrero won a Cruiserweight Open match when he pinned Jimmy Wang Yang, thus winning the Cruiserweight Championship from Gregory Helms. On June 24, Guerrero retained his title against Wang Yang at Vengeance: Night of Champions. At The Great American Bash, he lost the Cruiserweight title in a Cruiserweight Open when Hornswoggle pinned Jamie Noble.
Guerrero then turned his attention to Rey Mysterio, whom he had put out of action, in storyline, in 2006. Before Mysterio's return at SummerSlam, Guerrero mocked Mysterio's knee injury and taunted him during matches. He was, however, unable to defeat Mysterio at the pay-per-view. Guerrero then lost an "I Quit" rematch to Mysterio, after Mysterio assaulted his left knee with a steel chair. This allowed Guerrero to have time off to serve his suspension for violating the WWE Wellness Policy.
Guerrero remained inactive until the December 18, 2007 episode of ECW, where he appeared after the main event between WWE United States Champion Montel Vontavious Porter and ECW Champion CM Punk, and attacked the vulnerable Punk, sending a message that he wanted a title shot. Guerrero challenged Punk to several matches until he finally won the third after interference from World Heavyweight Champion Edge to earn a championship match. On the January 22, 2008 episode of ECW, Guerrero defeated Punk in a no disqualification match to win the ECW Championship following interference from Edge. In the process, he proclaimed Edge and company as his "familia". He then successfully defended his title against Punk at No Way Out and on the March 4 episode of ECW.
At WrestleMania XXIV, Guerrero lost the ECW Championship to Kane in a record eleven seconds. Shortly afterward, Bam Neely debuted to act as his bodyguard. Guerrero lost a rematch against Kane at Backlash and also failed to become the number one contender at One Night Stand. After Edge turned on La Familia, Guerrero returned to singles and tag team action with Neely. He also failed to regain the ECW Championship at Unforgiven in a Championship Scramble match, and later against champion Matt Hardy.
Guerrero was drafted to the Raw brand as part of the 2009 Supplemental Draft. He then became involved in the feud between Vickie Guerrero and Santino Marella. At Extreme Rules, Guerrero and Vickie were defeated by Marella in a Hog Pen match. Upon Vickie's departure from WWE, Guerrero continued to feud with Marella and defeated him on June 18 episode of WWE Superstars. Guerrero next feuded with Hornswoggle, where the two faced off in various types of matches (in which a handicap of some sort was imposed on Guerrero by the various celebrity guests left in charge of Raw every week), with Hornswoggle gaining the wins. Guerrero finally picked up a win when he teamed with Chris Masters to defeat Hornswoggle and Santino Marella in a tag team match on September 28, 2009 episode of Raw.
As part of the 2010 WWE Supplemental Draft, Guerrero was drafted back to the SmackDown brand. He started an alliance with Dolph Ziggler, and the duo defeated Christian in a handicap match. On July 9 episode of SmackDown, Guerrero competed in a triple threat Money in the Bank qualifying match, along with Ziggler and MVP. Throughout the match, it became apparent that Vickie Guerrero (Ziggler's manager) had told Guerrero and Ziggler to work together to ensure Ziggler qualified for the match. During the match, however, when both MVP and Ziggler were down, Guerrero attempted to pin MVP to win the match himself, turning his back on Vickie and Ziggler, thus ending the alliance.
On March 8, Guerrero was announced as the NXT Pro to Darren Young for the fifth season. On the May 6, 2011 episode of SmackDown, Guerrero commentated on a match between Tyson Kidd and Sin Cara, which Sin Cara won. On the 13 May episode of SmackDown, Guerrero aided Sin Cara in his match against Daniel Bryan. At Over The Limit, Sin Cara defeated Guerrero, and again on SmackDown to end their feud. Afterward, Guerrero mainly appeared on NXT with Darren Young. His last match in WWE was teaming up with JTG and Young against Yoshi Tatsu, Conor O'Brian and Vladimir Kozlov on NXT in a losing effort. On June 25, 2011, at his request, Guerrero was released by WWE, ending his 10-year tenure there.