On 26 March 1973, André made his WWE debut as a "face", defeating Buddy Wolfe in New York's Madison Square Garden.

By the time Vince McMahon, Jr. began to expand his promotion to the national level in the early 1980s, André wrestled exclusively for WWF in the USA, while still holding international engagements. André was mentioned in the 1974 Guinness Book of World Records as the highest paid wrestler in history up to that time. He had earned $400,000 in one year alone during the early 1970s.

André was one of WWF's most beloved "babyfaces" throughout the 1970s and early 1980s. As such, Gorilla Monsoon insisted that André was never defeated for 15 years by pinfall or submission prior to WrestleMania III. This, however, is not true. André actually had lost cleanly in matches outside of the parameters of WWF; a pinfall loss in Mexico to Canek in 1984 and in Japan a submission loss to Antonio Inoki in 1986. He also went sixty-minute time limit draws with the two other major world champions of the day, Harley Race and Nick Bockwinkel.

One of André's feuds pitted him against the Mongolian terror Killer Khan, who was managed by Freddie Blassie. According to the storyline, Khan had broken André's ankle during a match in Rochester, New York by leaping off the top rope and crashing down upon it with his knee-drop. After a stay at Beth-Israel Hospital in Boston, André returned with payback on his mind. On 14 November 1981 at the Philadelphia Spectrum, André exacted revenge by destroying Khan in what was billed as a "Mongolian Stretcher Match", in which the loser must be taken to the dressing room on a stretcher. In reality, André had snapped his ankle getting out of bed one morning. The injury and subsequent rehabilitation was worked into the existing André/Khan storyline.

Another feud involved a man who considered himself to be "the true giant" of wrestling: Big John Studd. Throughout the early to mid-1980s, André and Studd fought all over the world, battling to try and determine who the real giant of wrestling was. In December 1984, Studd took the feud to a new level, when he and partner Ken Patera knocked out André during a televised tag team match and proceeded to cut off André's hair. André had the last laugh at the first WrestleMania on 31 March 1985 at Madison Square Garden. André conquered Studd in a $15,000 Body Slam Challenge. After slamming Studd, he attempted to give the $15,000 prize to the fans, before having the bag stolen from him by his future manager Bobby "The Brain" Heenan.

The following year, at WrestleMania 2 on 7 April 1986, André continued to display his dominance by winning a twenty-man battle royal that featured top NFL stars and wrestlers. André last eliminated Bret Hart to win the contest. Afterward, André continued his feud with Studd and King Kong Bundy. André was suspended after a no-show; he returned under a mask as "The Giant Machine" part of a team with "Big Machine" (Robert Windham) and "Super Machine" (Bill Eadie) (The Machines gimmick was copied from New Japan Pro Wrestling character "Super Strong Machine", played by Japanese wrestler Junji Hirata).[6] Soon afterwards, Giant Machine disappeared, and André was reinstated, to the approval of Bobby "The Brain" Heenan.

André was turned heel in 1987 so that he could face Hulk Hogan for the WWF World Heavyweight Championship in the main event of WrestleMania III. In early 1987, Hogan was presented a trophy for being the WWF World Heavyweight Champion for three years. André came out to congratulate him. Shortly afterward, André was presented a slightly smaller trophy for being "undefeated in WWF for fifteen years." In actuality, André had suffered a handful of countout and disqualification losses in WWF but had never been pinned or forced to submit in a WWF ring. Hogan came out to congratulate André and ended up being the focal point of the interview. A visibly annoyed André walked out in the midst of Hogan's speech. Then, on an edition of "Piper's Pit", Hogan was confronted by Bobby Heenan. Heenan announced that his new protege was André, who then challenged Hogan to a title match at WrestleMania III, ripping the t-shirt and crucifix from Hogan.

At WrestleMania III, he was billed at 525 lb (238 kg), and the stress of that 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. Hogan won the match after body slamming André, followed by Hogan's running leg drop finisher. Years later, Hogan claimed that André was so heavy, he felt more like 700 lb (320 kg), and that he actually tore his latissimus dorsi muscle slamming him. Another famous story about the match is that no one knew if André would lose the match. André had agreed to lose the match some time before, mostly for health reasons, though he almost pinned Hogan (albeit unintentionally) in the early goings of the match. Contrary to popular belief, it was not the first time that Hogan had successfully bodyslammed André in a WWF match. A then-heel Hogan bodyslammed a then-face André early in a match in Hamburg, Pennsylvania on 13 September 1980, though André was much lighter and more athletic at the time. This, of course, back in the territorial days of wrestling three years before WWF began its national expansion (André had also previously allowed Harley Race, Kamala, and Stan Hansen to slam him. By the time WrestleMania III had rolled around, the WWF had gone national, giving more meaning to the André-Hogan match that took place then. The feud between André and Hogan simmered during the summer of 1987, even as Roussimoff's health declined. The feud would begin heating up again when each wrestler was named the captain of rival teams at the inaugural Survivor Series event. André's team won the main event after André pinned Bam Bam Bigelow.

In the meantime, "The Million Dollar Man" Ted DiBiase failed to persuade Hogan to sell him the WWF World Championship. After failing to defeat Hogan in a subsequent series of matches, DiBiase turned to André to win it for him. Acting as his hired gun, André won the WWF title from Hogan on 5 February 1988 in a match where it was later revealed appointed referee Dave Hebner was "detained backstage", and a replacement who DiBiase paid to get plastic surgery to look like Dave (in reality, his twin brother Earl Hebner), made a three count on Hogan while his shoulders were off the mat. After winning, André "sold" the title to DiBiase; the transaction was declared invalid by then-WWF President Jack Tunney and the title was vacated. This was shown on WWF's NBC program The Main Event. At WrestleMania IV, André and Hulk Hogan fought to a double disqualification in a WWF title tournament match (with the idea in the storyline saying that André was again working on DiBiase's behalf in giving DiBiase a clearer path in the tournament). Afterward, André and Hogan's feud died down after a steel cage match held at WrestleFest on 31 July 1988 in Milwaukee. He and DiBiase also wrestled Hogan and Randy "Macho Man" Savage in the main event of SummerSlam; the DiBiase-André team lost, despite apparently having referee Jesse "the Body" Ventura on their side.

André's next major feud was against Jake "The Snake" Roberts. In this storyline, it was said André was deathly afraid of snakes, something Roberts exposed on Saturday Night's Main Event when he threw his snake, Damien, on the frightened André; as a result, André suffered a kayfabe mild heart attack and vowed revenge. During the next few weeks, Roberts frequently walked to ringside during André'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 André.

During the late summer and fall of 1989, André engaged in a brief feud with then-Intercontinental champion The Ultimate Warrior, where the younger Warrior regularly squashed the aging André. Earlier in 1989, André and the returning Big John Studd reprized their feud, this time with Studd as a face and André as the heel.

André won the World Tag Team Championship with his partner Haku (known collectively as The Colossal Connection) from Demolition on 13 December 1989. Managed by Bobby Heenan, they lost their titles at WrestleMania VI back to Demolition on 1 April 1990. After the match, a furious Heenan slapped André; he responded by knocking Heenan out, much to the delight of the fans. André went into the match as a heel, and left as a face.

Community content is available under CC-BY-SA unless otherwise noted.