Slaughter signed with the WWF and was pushed as a villainous character. Between 1980 and 1981, Slaughter wrestled in the WWF under the guidance of the Grand Wizard. He quickly rose to the status of number one contender on the strength of his "cobra clutch" challenges where he would seat wrestlers in a chair in the ring, and apply the hold, offering $5,000 to anyone who could break it. He would eventually face Bob Backlund for the World Wrestling Federation Heavyweight Championship across the WWF territory in 1980, earning two-or-three main event matches in most markets. Slaughter was the only WWF-based challenger not to do the honors for Backlund at MSG (Backlund defeated him at the Meadowlands, but never in the Garden). Slaughter then engaged in a feud with Pat Patterson, which stemmed from Slaughter calling Patterson "yellow" and offering him $10,000 (double the usual amount) to try to break the cobra clutch. Patterson accepted on television and was escaping from the hold when Slaughter released it and put a beat-down on Patterson, starting a hot feud which culminated in an "Alley Fight" in New York City's Madison Square Garden between the two. in 1983, Slaughter was a top contender to Bob Backlund's WWF Championship. However, his career took off after he turned face and defended America's honor against the hated Iron Sheik in 1984. Slaughter and the Iron Sheik engaged in many matches throughout 1984, culminating in a boot camp match which took place before a sold out Madison Square Garden that summer. However, with the emergence of Hulk Hogan as the WWF Champion and lead face within the company, Slaughter left.
After Wrestlemania VI, Slaughter sent a letter to Vince McMahon saying he loved the program and was interested in returning. McMahon told him, he wanted a heel and Slaughter agreed, this gimmick was that Slaughter turned on America and was angry that Nikolai Volkoff was accepted by America and America had "Gone Soft" and was doing Anti-America promos.
As the political situation in the Middle East was growing increasingly tense, the decision was made to have Slaughter support the Iraqi cause. Slaughter aligned himself with a kayfabe Iraqi military general, General Adnan, and entered a feud with Volkoff (which saw Slaughter win the majority of their encounters at house shows), leading to a match at that year's Survivor Series which saw The Alliance (Volkoff, Tito Santana, and The Bushwhackers) defeat The Mercenaries (Slaughter, Boris Zhukov, and The Orient Express).
As 1990 ended Slaughter began challenging for the WWF Championship that had been held by The Ultimate Warrior since WrestleMania VI. Slaughter got his chance at the Royal Rumble in January 1991 and defeated the Warrior when Randy "Macho King" Savage, who had also been feuding with the Warrior at the time, struck the champion in the head with his royal scepter. Slaughter thus became the thirteenth WWF Champion and was immediately challenged by Royal Rumble winner Hulk Hogan, who was furious that Slaughter had (kayfabe) desecrated the American flag (offscreen) as part of his victory celebration. Hogan demanded a match against Slaughter at WrestleMania VII in Los Angeles, California, and Slaughter accepted. Slaughter was defeated by Hogan, thus losing his championship.
After WrestleMania Slaughter introduced his newest ally, Colonel Mustafa (The Iron Sheik, Slaughter's old nemesis). Slaughter and company went on to feud with Hogan for months, including having a three-on-two handicap match at SummerSlam 1991, which saw the team of Hulk Hogan and the Ultimate Warrior prevail over Slaughter, Adnan, and Mustafa.
After finishing the Hogan feud, Slaughter became a face again, appearing in vignettes next to American landmarks, saying "I want my country back." During an episode of Superstars, "Hacksaw" Jim Duggan was under attack from The Nasty Boys, and Slaughter made the save. Duggan and Slaughter teamed up to defeat the Nasty Boys and continued to team over the next several months. Slaughter quietly disappeared from WWF TV following a loss to Nailz in October 1992.
After a hiatus, he returned to WWF television on the August 4, 1997 episode of Raw Is War to assume the role of on-air commissioner. Initially popular, he eventually became the target of D-Generation X, who called him "Sgt. Slobber". On an episode of Raw Is War, he put Shawn Michaels and Triple H in a match for Michaels' European Championship. Michaels dropped the belt to Helmsley, by lying down in the ring. Slaughter challenged Triple H to a Boot Camp match at the December pay-per-view, which he lost. His feud with Triple H continued into WrestleMania XIV where he handcuffed himself to Chyna to prevent her from interfering in Helmsley's match against Owen Hart. Slaughter's efforts ultimately proved futile as Chyna threw powder in his eyes, interfered in the match anyway, and hurled Slaughter into the front row.
In 1998, Slaughter turned heel, and joined Vince McMahon along with Gerald Brisco and Pat Patterson, became the on-screen lackeys of McMahon; running errands for him and dishing out punishment to McMahon's rivals, namely Stone Cold Steve Austin. In late 1998, Slaughter relinquished the role of commissioner to Shawn Michaels and largely disappeared from television.
Slaughter still appeared from time to time in the ring, mostly at house shows. He appeared on Raw to put over younger wrestlers, such as Kurt Angle and Randy Orton. Slaughter also made an appearance at WrestleMania X-Seven, in the Gimmick Battle Royal, which was won by The Iron Sheik. Slaughter got his revenge after the match by locking the Sheik in the cobra clutch. He also appeared on both Raw and SmackDown on occasion during the Invasion storyline in non-wrestling roles, usually in conjunction with Vince McMahon.
He was inducted into the WWE Hall of Fame on March 13, 2004, the night before WrestleMania XX by long-time friend Pat Patterson.
He made a special appearance on the June 13, 2005 episode of Raw to challenge Chris Masters in his "Master Lock Challenge", which Slaughter lost. Then, he returned again on the December 5 episode of Raw, where he and Michael Hayes confronted Edge. He also appeared on the July 4, 2005 episode of Raw for a "Diva Boot Camp" segment, as a part of the 2006 Diva Search Competition.
He re-appeared on the October 2 episode of Raw, defeating Nicky from the Spirit Squad with a roll-up when D-Generation X distracted him from up on the Titantron. Slaughter appeared on the October 23 Raw in the corner of Ric Flair as he faced Kenny of the Spirit Squad. After Kenny cheated to gain the victory, Slaughter, Dusty Rhodes, and Roddy Piper cleared the tag champions from the ring. Slaughter was one of three options between himself, Roddy Piper, and Dusty Rhodes that fans could vote for as a tag partner for Ric Flair at Cyber Sunday, but did not win the vote. At Survivor Series, Slaughter teamed with Flair, Ron Simmons, and Dusty Rhodes to take on four members of the Spirit Squad in a Survivor Series match. Slaughter was eliminated in the match, but his team won, with Flair as the sole survivor.
On December 18, 2006, Slaughter participated in a 30-Man Battle Royal for a chance to face John Cena in the main event for the WWE Championship, but he was eliminated from the match and did not get the title shot. At the Vengeance: Night of Champions pay-per-view in June 2007, he faced Deuce 'n Domino for the WWE Tag Team Championship, alongside Jimmy Snuka. They were unsuccessful in their attempt for the titles. He challenged Randy Orton on the July 30 episode of Raw, only to become another victim of the "Legend Killer", and was wheeled out on a stretcher. On Raw XV, the 15th-anniversary Raw special on December 10, 2007, Slaughter participated in the 15th Anniversary Battle Royal. On March 31, 2008, on an episode of Raw, Slaughter paid tribute to long time friend Ric Flair at the end of the show. He appeared on Raw's 800th episode in Kung Fu Naki's dance off and also made an appearance in the Slammy Awards.
Slaughter, who had been working as a producer for WWE for the past several years, was released from his backstage producer duties with the company on January 13, 2009. He was the special guest host on Raw on August 10, 2009 where he made fun of Canadians and saying how the USA is the greatest country in the world. He made an appearance on the Decade of SmackDown on October 2, 2009 where he had an altercation with the Iron Sheik about which country was the greatest, USA or Iran. His last televised match was on December 31, 2012 against Antonio Cesaro in a losing effort.