On March 26, 1973, Andre debuted in the World Wide Wrestling Federation (later World Wrestling Federation) as a fan favorite, defeating Buddy Wolfe in New York's Madison Square Garden.
Andre was one of professional wrestling's most beloved "babyfaces" throughout the 1970s and early 1980s. As such, Gorilla Monsoon often stated that he had not been defeated in 15 years by pinfall or submission prior to WrestleMania III.
In 1976, Andre fought professional boxer Chuck Wepner in an unscripted boxer-versus-wrestler fight. The wild fight was shown via telecast as part of the undercard of the Muhammad Ali versus Antonio Inoki fight and ended when he threw Wepner over the top rope and outside the ring and won via count out.
In 1980 he feuded with Hulk Hogan, when, unlike their more famous matches in the late 1980s, Hogan was the villain and Andre was the hero, wrestling him at Shea Stadium's Showdown at Shea and in Pennsylvania, where after he pinned Hogan to win the match. Hogan bodyslammed him much like their legendary WrestleMania III match in 1987. The feud continued in Japan in 1982 and 1983 with their roles reversed and with Antonio Inoki also involved. In 1982, Vince McMahon, Sr. sold the World Wide Wrestling Federation to his son, Vince McMahon, Jr.
One of Andre's feuds pitted him against the "Mongolian Giant" Killer Khan. According to the storyline, Khan had snapped Andre's ankle during a match on May 2, 1981, in Rochester, New York, by leaping off the top rope and crashing down upon it with his knee-drop. The two battled on July 20, 1981, at Madison Square Garden in a match that resulted in a double disqualification. Their feud continued as fans filled arenas up and down the east coast to witness their matches. On November 14, 1981, at the Philadelphia Spectrum, he decisively defeated Khan in what was billed as a "Mongolian stretcher match", in which the loser must be taken to the dressing room on a stretcher. The same type of match was also held in Toronto. In early 1982 the two also fought in a series of matches in Japan with Arnold Skaaland in Andre's corner.
Another feud involved a man who considered himself to be the "true giant" of wrestling: Big John Studd. Throughout the early to mid-1980s, Andre and Studd fought all over the world, battling to try to determine who the real giant of wrestling was. In 1984, Studd took the feud to a new level when he and partner Ken Patera knocked out Andre during a televised tag-team match and proceeded to cut off his hair. After gaining revenge on Patera, Andre met Studd in a "body slam challenge" at the first WrestleMania, held March 31, 1985, at Madison Square Garden in New York City. Andre slammed Studd to win the match and collect the $15,000 prize, then proceeded to throw cash to the fans before having the bag taken from him by Studd's manager, Bobby "The Brain" Heenan.
The following year, at WrestleMania 2, on April 7, 1986, Andre continued to display his dominance by winning a twenty-man battle royal which featured top National Football League stars and wrestlers. He last eliminated Bret Hart to win the contest.
After WrestleMania 2, Andre continued his feud with Studd and King Kong Bundy. During this time, Andre requested a short leave of absence for health reasons. To explain his absence, a storyline was developed in which Heenan—suggesting that Andre was secretly afraid of Studd and Bundy, whom Heenan bragged were unbeatable—challenged Andre and a partner of his choosing to wrestle Studd and Bundy in a televised tag-team match. When Andre failed to show, WWF president Jack Tunney indefinitely suspended him. Later in the summer of 1986, upon Andre's return, he began wearing a mask and competing as the "Giant Machine" in a stable known as the Machines. (Big Machine and Super Machine were the other members. The WWF's television announcers sold the Machines as "a new tag-team from Japan" and claimed not to know the identities of the wrestlers, even though it was obvious to fans that it was Andre competing as the Giant Machine. Heenan, Studd, and Bundy complained to Tunney, who eventually told Heenan that if it could be proven that Andre and the Giant Machine were the same person, Andre would be fired. Andre thwarted Heenan, Studd, and Bundy at every turn. Then, in late 1986, the Giant Machine "disappeared," and Andre was reinstated.
Andre turned heel in early 1987 to be the counter to the biggest "babyface" in professional wrestling at that time, Hulk Hogan. On an edition of Piper's Pit in 1987, Hogan was presented a trophy for being the WWF World Heavyweight Champion for three years; Andre came out to congratulate him, shaking Hogan's hand with a strong grip, which surprised the Hulkster. On the following week's Piper's Pit, Andre was presented a slightly smaller trophy for being "the only undefeated wrestler in wrestling history." Although he had suffered a handful of countout and disqualification losses in WWF, he had never been pinned or forced to submit in a WWF ring. Hogan came out to congratulate him and ended up being the focal point of the interview. Apparently annoyed, he walked out in the midst of Hogan's speech. A discussion between Andre and Hogan was scheduled, and on a Piper's Pit that aired February 7, 1987, the two met. Hogan was introduced first, followed by Andre, who was led by longtime rival Bobby Heenan.
Speaking on behalf of his new protégé, Heenan accused Hogan of being Andre's friend only so he would not have to defend his title against him. Hogan tried to reason with Andre, but his pleas were ignored as he challenged Hogan to a match for the WWF World Heavyweight Championship at WrestleMania III. Hogan was still seemingly in disbelief as to what Andre was doing, prompting Heenan to say "You can't believe it, maybe you'll believe this, Hogan" before Andre ripped off the T-shirt and crucifix from Hogan, with the crucifix scratching Hogan's chest, causing him to bleed.
Following Hogan's acceptance of his challenge on a later edition of Piper's Pit, the two were part of a 20-man over-the-top rope battle-royal on the 14 March edition of Saturday Night's Main Event at the Joe Louis Arena in Detroit. Although the battle royal was won by Hercules, Andre claimed to have gained a psychological advantage over Hogan when he threw the WWF World Heavyweight Champion over the top rope. The match, which was actually taped on February 21, 1987, aired only two weeks before WrestleMania III to make it seem like Hogan had met his match in André the Giant.
At WrestleMania III, he was billed at 240 kg (520 lb), and the stress of such immense weight on his bones and joints resulted in constant pain. After recent back surgery, he was also wearing a brace underneath his wrestling singlet. In front of a record crowd, Hogan won the match after body-slamming Andre (later dubbed "the bodyslam heard around the world"), followed by Hogan's running leg drop finisher.
The feud between Andre and Hogan simmered during the summer of 1987, as Andre's health declined. The feud began heating up again when wrestlers were named the captains of rival teams at the inaugural Survivor Series event. During their approximately one minute of battling each other during the match, Hogan dominated Andre and was on the brink of knocking him from the ring, but was tripped up by his partners, Bundy and One Man Gang, and would be counted out. Andre went on to be the sole survivor of the match, pinning Bam Bam Bigelow before Hogan returned to the ring to attack André and knock him out of the ring. Andre later got revenge when, after Hogan won a match against Bundy on Saturday Night's Main Event, he snuck up from behind and began choking Hogan to the brink of unconsciousness, not letting go even after an army of seven face-aligned wrestlers ran to the ring to try to pull him away; it took Hacksaw Jim Duggan breaking a piece of wood over his back (which he no-sold) for him to let go, after which Hogan was pulled to safety. As was the case with the SNME battle royal a year earlier, the series of events was one of the pieces that helped build interest in a possible one-on-one rematch between Hogan and Andre , and to make it seem that Andre was certain to win easily when they did meet.
In the meantime, the "Million Dollar Man" Ted DiBiase failed to persuade Hogan to sell him the WWF World Heavyweight Championship. After failing to defeat Hogan in a subsequent series of matches, DiBiase turned to Andre to win it for him. The earlier attack and DiBiase's insertion into the feud set up the Hogan-Andre rematch on The Main Event, to air 5 February 1988, on a live broadcast on NBC. Acting as his hired gun, Andre won the WWF World Heavyweight Championship from Hogan (his first singles title) in a match where it was later revealed that appointed referee Dave Hebner was "detained backstage", and a replacement (whom Hogan afterwards initially accused of having been paid by DiBiase to get plastic surgery to look like Dave, but was revealed to have been his evil twin brother, Earl Hebner), made a three count on Hogan while his shoulders were off the mat.
After winning, Andre "sold" the title to DiBiase; the transaction was declared invalid by then-WWF president Jack Tunney and the title was declared vacant. At WrestleMania IV, Andre and Hulk Hogan fought to a double disqualification in a WWF title tournament match (with the idea in the storyline saying that Andre was again working on DiBiase's behalf in giving DiBiase a clearer path in the tournament). Afterward, Andre and Hogan's feud died down after a steel cage match held at WrestleFest on July 31, 1988, in Milwaukee.
At the inaugural SummerSlam pay-per-view held at Madison Square Garden, Andre and DiBiase (billed as The Mega Bucks) faced Hogan and WWF World Heavyweight Champion "Macho Man" Randy Savage (known as The Mega Powers) in the main event, with Jesse "The Body" Ventura as the special guest referee. During the match, the Mega Powers' manager, Miss Elizabeth, distracted the Mega Bucks and Ventura when she climbed up on the ring apron, removed her yellow skirt and walked around in a pair of red panties. This allowed Hogan and Savage time to recover and eventually win the match with Hogan pinning DiBiase. Savage forced Ventura's hand down for the final three-count, due to Ventura's character historically being at odds with Hogan, and his unwillingness to count the fall.
Concurrent with the developing feud with the Mega Powers, Andre was placed in a feud with Jim Duggan, which began after Duggan knocked out Andre with a two-by-four board during a television taping. Despite Duggan's popularity with fans, Andre regularly got the upper hand in the feud.
Andre's next major feud was against Jake "The Snake" Roberts. In this storyline, it was said Andre was afraid of snakes, something Roberts exposed on Saturday Night's Main Event when he threw his snake, Damien, on the frightened Andre; as a result, he suffered a kayfabe mild heart attack and vowed revenge. During the next few weeks, Roberts frequently walked to ringside during Andre's matches, causing him to run from the ring in fright (since he knew what was inside the bag). Throughout their feud (which culminated at WrestleMania V), Roberts constantly used Damien to gain a psychological edge over the much larger and stronger Andre.
In 1989, Andre and the returning Big John Studd briefly reprised their feud, beginning at WrestleMania V, when Studd was the referee in the match with Roberts, this time with Studd as a face and Andre as the heel. During the late summer and Autumn of 1989, he engaged in a brief feud, consisting almost entirely of house shows, with then-Intercontinental Champion The Ultimate Warrior. The younger Warrior, WWF's rising star, regularly squashed the aging Andre in an attempt to showcase his star quality and promote him as the "next big thing".
In late 1989, Andre was joined with fellow Heenan Family member Haku to form a new tag team called the Colossal Connection. The Colossal Connection immediately targeted WWF Tag Team Champions Demolition (who had recently won the belts from the Brain Busters). At a television taping on December 13, 1989, the Colossal Connection defeated Demolition to win the titles. Andre and Haku successfully defended their title, mostly against Demolition, until WrestleMania VI on April 1, 1990, when Demolition took advantage of a mistimed move by the champions to regain the belts. After the match, a furious Heenan blamed Andre for the title loss and after shouting at him, slapped him in the face; an angry Andre responded with a slap of his own that sent Heenan staggering from the ring. Andre also caught Haku's kick attempt, sending him reeling from the ring as well, prompting support for Andre and turning him face for the first time since 1987. Due to his ongoing health issues, Andre was not able to wrestle at the time of Wrestlemania VI and Haku actually wrestled the entire match against Demolition without tagging him in.
On weekend television shows following WrestleMania VI, Bobby Heenan vowed to spit in Andre's face when he came crawling back to the Heenan Family. However Andre would wrestle one more time with Haku, teaming up to face Demolition on a house show in Honolulu, HI, on April 10; Andre was knocked out of the ring and The Colossal Connection lost via countout. After the match, Andre and Haku would fight each other, marking the end of the team.
The following month, on November 30 at a house show in Miami, Florida, the World Wrestling Federation announced his return as a participant in the 1991 Royal Rumble (to be held in Miami, FL two months later). Andre was also mentioned as a participant on television but would ultimately back out due to a leg injury.
His on-air return finally took place at the WWF's Super-Stars & Stripes Forever USA Network special on March 17, 1991, when he came out to shake the hand of The Big Boss Man after an altercation with Mr. Perfect. The following week, at WrestleMania VII, he came to the aid of the Boss Man in his match against Mr. Perfect. Andre finally returned to action on April 26, 1991, in a six-man tag-team matchup when he teamed with the Rockers in a winning effort against Mr. Fuji and the Orient Express at a house show in Belfast, Northern Ireland. On May 10 he participated in a 17-man battle-royal at a house show in Detroit (won by Kerry Von Erich). His last major WWF storyline following WrestleMania VII had the major heel managers (Bobby Heenan, Sensational Sherri, Slick, and Mr. Fuji) trying to recruit Andre one-by-one, only to be turned down in various humiliating ways (e.g. Heenan had his hand crushed, Sherri received a spanking, Slick got locked in the trunk of the car he was offering to Andre and Mr. Fuji got a pie in his face). Finally, Jimmy Hart appeared live on WWF Superstars to announce that he had successfully signed Andre to tag-team with Earthquake. However, when asked to confirm this by Gene Okerlund, Andre denied the claims. This led to Earthquake attacking Andre from behind (injuring his knee). Jimmy Hart would later get revenge for the humiliation by secretly signing Tugboat and forming the Natural Disasters. This led to Andre's final major WWF appearance at SummerSlam 1991, where he seconded the Bushwhackers in their match against the Disasters. Andre was on crutches at ringside, and after the Disasters won the match, they set out to attack him, but the Legion of Doom made their way to ringside and got in between them and the Giant, who was preparing to defend himself with one of his crutches. The Disasters left the ringside area as they were outnumbered by the Legion of Doom, the Bushwhackers and Andre, who struck both Earthquake and Typhoon (the former Tugboat) with the crutch as they left. His final WWF appearance came at a house show in Paris, France, on October 9. He was in Davey Boy Smith's corner as the Bulldog faced Earthquake. Davey Boy hit Earthquake with Andre's crutch, allowing Smith to win.
His last U.S. television appearance was in a brief interview on World Championship Wrestling's (WCW) Clash of the Champions XX special that aired on TBS on 2 September 1992.
On January 27, 1993, Andre the Giant passed away. In 1993, when the then-World Wrestling Federation created the WWF Hall of Fame, André the Giant was the inaugural and sole inductee in the class of 1993.