Santana joined the World Wrestling Federation defeating Mike Hall in his debut match on Championship Wrestling in 1979. He teamed with Ivan Putski to defeat Johnny Valiant and Jerry Valiant for the WWF Tag Team Championship at Madison Square Garden in October 1979. The duo held the titles for close to six months before losing to the Wild Samoans in April 1980. Santana left the promotion later that year.
Santana wrestled in the American Wrestling Association (AWA) from 1980 to 1982. Matches he had in the AWA include two matches he had against Nick Bockwinkel in St Paul, Minnesota, on March 1, 1981, and in Winnipeg, Manitoba, on May 13, 1982 (Bockwinkel won both matches by cheating). Santana also wrestled Blackie Guzman, and teamed with Rick Martel against the High Flyers on August 29, 1982, in St. Paul Minnesota. Santana and Martel lost the match.
Santana returned to the WWF in 1982. He made his televised return on the May 14, 1983 episode of Championship Wrestling by defeating José Estrada. In 1983, Santana fought the Iron Sheik to a double-disqualification for the WWF World Heavyweight Championship at the Philadelphia Spectrum. He then engaged in a lengthy feud with WWF Intercontinental Heavyweight Champion, the Magnificent Muraco. Santana finally won the title on February 11, 1984, becoming the first Mexican-American wrestler to win the Intercontinental Heavyweight Championship. After successfully defending the Intercontinental Heavyweight Championship against Muraco, Santana was targeted by Greg "the Hammer" Valentine, and in September 1984 in London, Ontario, Canada, Valentine defeated Santana to win the title. Soon after, the storyline had Valentine injuring Santana's knee and putting Santana out of action for several months.
Santana returned in December 1984 and set his sights on getting the Intercontinental title back from Valentine. During this time, he started using Valentine's finishing hold, the figure-four leglock and also wrestled in tag-team competition with Blackjack Mulligan. Santana wrestled at the first WrestleMania, at Madison Square Garden, in March 1985, and in the opening match defeated a masked wrestler known as the Executioner ("Playboy" Buddy Rose), making him submit to the figure four in 4:05. Santana made an appearance in the ring later in the card during the Intercontinental Heavyweight Championship match between Valentine and Santana's friend the Junkyard Dog. Wearing street clothes, Santana rushed to the ring to inform referee Dick Kroll that Valentine had used his feet on the ropes to help pin the JYD. Despite having already called for the bell, Kroll restarted the match and an incensed Valentine was counted out as he did not get back into the ring to continue.
Santana and Valentine went on to wrestle a memorable series of singles and tag team matches with neither gaining the upper hand. They wrestled in a variety of different types of matches such as regular title matches, no disqualification matches, and lumberjack matches. The pair also faced off in tag team competition with Santana teaming with the Junkyard Dog and Valentine teaming with Brutus Beefcake in a team that would become known as the Dream Team.
Santana recaptured the Intercontinental Heavyweight Championship from Valentine in a brutal steel cage match in Baltimore on July 6, 1985. After the match, Valentine, incensed over losing the belt, destroyed it by repeatedly bashing it against the steel cage, forcing the WWF to get a new Intercontinental Heavyweight Championship belt. Santana would hold on to the title until February 8, 1986 when he lost it to "Macho Man" Randy Savage at the Boston Garden, after Savage knocked him out with a foreign object he had hidden in his tights that went unnoticed by referee Danny Davis.
Although Santana lost the Intercontinental title before the WWF's storyline that Davis was a corrupt official who clearly favored the heels, the WWF used Santana losing the belt because of Davis' bias to include him in a six-man tag team match at WrestleMania III on March 29, 1987, where he teamed with the British Bulldogs (Dynamite Kid and Davey Boy Smith) against the WWF Tag Team Champions the Hart Foundation (Bret "Hitman" Hart and Jim "the Anvil" Neidhart) and their new partner, former referee "Dangerous" Danny Davis (who had previously wrestled for the WWF as a masked jobber named "Mr. X"). Davis had also been the assigned referee when the Harts stole the WWF Tag Team Championship from the Bulldogs in January 1987, allowing the Harts to double team Davey Boy throughout the entire match after their manager "the Mouth of the South" Jimmy Hart had knocked Dynamite out with his megaphone. The story for WrestleMania III being that the Bulldogs and Santana wanted revenge on Davis as the one responsible for losing their respective titles. The Harts and Davis won the match when Davis used Jimmy Hart's megaphone to 'knock out' and pin Smith.
Santana made a second appearance during Wrestlemania III when he came to the ring and attacked manager Slick after his man "the Natural" Butch Reed had defeated Koko B. Ware. Santana, in response to previous attacks by Slick, tore the clothing from Slick who managed to scamper back to the locker room with his suit in tatters. Following this, Reed entered the ring to fight off Santana but was sent from the ring by a double dropkick from Santana and Ware.
Santana formed the popular tag team Strike Force with Canadian Rick Martel in August 1987. They defeated The Hart Foundation for the WWF Tag Team championship on a televised edition of WWF Superstars of Wrestling when Martel made Jim Neidhart submit to a Boston crab. Strike Force held them for five months before losing to Demolition at WrestleMania IV. Due to a neck injury inflicted on Martel shortly after the loss, the team was inactive for several months. Immediately after the injury, Santana introduced a new tag team to the WWF, The Powers of Pain (The Barbarian and The Warlord), two big, muscled up power wrestlers whom he briefly managed. The Powers were introduced as mercenaries to help Martel and Santana gain revenge on Demolition for both the title loss and the injury to Martel. The Powers would later find more permanent management with The Baron before finally turning heel at the 1988 Survivor Series by stealing away Demolition's manager Mr. Fuji, leaving the champions as babyfaces.
Martel returned at the Royal Rumble in 1989 and reunited with Santana. However, in their WrestleMania V match against The Brain Busters (Tully Blanchard and Arn Anderson), Martel turned on Santana during the match after accidentally being hit by Santana's Flying forearm smash. Martel refused to tag in and walked back to the dressing room leaving Santana to face both opponents alone (the Busters then easily defeated Tito with a Spike piledriver). In an interview with "Mean" Gene Okerlund immediately following the match, Martel called Santana a loser and said he was sick and tired of carrying him. His feud with the newly heel Martel would last throughout 1989, with both men on opposing teams at both SummerSlam and Survivor Series and Santana defeating Martel in the finals of the 1989 King of the Ring tournament. Santana even allied with his former archenemies Demolition against Martel, defeating him and The Fabulous Rougeaus in a six-man tag match on June 22, 1989 in Hartford, Connecticut.
After The Ultimate Warrior won the WWF World Heavyweight Championship from Hulk Hogan at WrestleMania VI and vacated the Intercontinental Heavyweight Championship, Santana took part in an eight-man tournament to name a new Intercontinental Champion. Santana made it to the finals, where he lost to Mr. Perfect. Following that loss, Santana occasionally teamed with Koko B. Ware.
At the 1990 Survivor Series, he teamed with Nikolai Volkoff and The Bushwhackers (Luke and Butch). He was the winner and sole survivor in the elimination-style match against Sgt. Slaughter, Boris Zhukov, and The Orient Express (Sato and Tanaka). As a result, Santana advanced to the final elimination match, teaming with Hulk Hogan and The Ultimate Warrior against Martel, "The Million Dollar Man" Ted DiBiase, The Warlord, and Power and Glory (Hercules and Paul Roma). Santana would eliminate The Warlord with his Flying forearm before being pinned by DiBiase. Santana would then wrestle at WrestleMania VII, losing to The Mountie in a little over a minute after being hit in the stomach by The Mountie's electrified cattle prod.
Later in 1991, Santana adopted a Spanish bullfighter gimmick and the nickname "El Matador" after he returned to the WWF. His first WrestleMania match under this gimmick was when he faced and lost to Shawn Michaels in the opening bout of WrestleMania VIII at the Hoosier Dome in Indianapolis. Santana wrestled under the "El Matador" gimmick through 1993, mostly as a jobber. This included a dark match loss to Papa Shango at SummerSlam which was held at the Wembley Stadium in London, England. Santana defeated friend and frequent tag team partner Virgil on a 1993 episode of Wrestling Challenge. As a sign of mutual respect between the two, both men embraced after the match.
Santana stopped appearing on WWF programming in North America, but he continued working on the WWF Summer tour in Europe and the international house show circuit through the course of August–September. In his final in-ring WrestleMania appearance, he defeated Papa Shango at WrestleMania IX in the untelevised opening match. Santana continued to wrestle through the first half of 1993 following WrestleMania IX, facing Razor Ramon, Adam Bomb, and Papa Shango. His final match was on August 13, 1993 in Wildwood, New Jersey, when he defeated Damian Demento.
Santana played a role in the formative years of ECW. He won the ECW Heavyweight Championship on August 8, 1993 by defeating former WWF rival Don Muraco, but forfeited the championship later that year to Shane Douglas.
Santana returned to the WWF as a commentator in the Spanish broadcast table in 1997. He called Monday Night Raw, as well as pay-per-view events. His last appearance doing Spanish commentary was at WrestleMania XIV.
On January 10, 2000, Santana made a one-time appearance in WCW. He defeated Jeff Jarrett in a Dungeon match on Nitro.
On March 13, 2004, he was inducted to the WWE Hall of Fame class of 2004, with an induction speech by his WrestleMania VIII opponent Shawn Michaels.
On the November 15, 2010 "Old School" episode of Raw, he ring-announced Alberto Del Rio.