In his American Wrestling Association (AWA) debut in 1969, Heenan debuted under the nickname of "The Brain". He took up managing the team of Nick Bockwinkel and Ray "The Crippler" Stevens, a duo which won their third AWA World Tag Team Championship under his leadership. While Bockwinkel and Stevens feuded with The Crusher and Dick the Bruiser, Bruiser famously called Heenan "Weasel"; this led to his rivals calling him "Weasel" throughout the rest of his wrestling career. The AWA was the starting point for the first incarnation of his eponymous heel stable, The Heenan Family, which initially consisted of Bockwinkel, Stevens, Bobby Duncum Sr., and Blackjack Lanza.
Later in 1975, Bockwinkel captured his first of several AWA World Heavyweight Championships, ending the seven-year reign of perennial champion and AWA promoter Verne Gagne. While Bockwinkel was AWA Champion in 1976, Lanza and Duncum captured the AWA World Tag Team Championship, making Heenan the first manager in history to simultaneously manage both a major promotion's singles and tag team champions.
In late 1979, Heenan returned to AWA and resumed managing Nick Bockwinkel to renewed championship success, including against Hulk Hogan in 1983. During AWA's tour of Japan in 1983, Heenan suffered a neck injury in a match with Atsushi Onita that would limit his in-ring ability going forward.
In 1984, Heenan left AWA to join the World Wrestling Federation (WWF). He was written out of AWA television when Wally Karbo announced on the September 28 AWA broadcast that Heenan had been suspended indefinitely by AWA President Stanley Blackburn for initiating a brawl with The Fabulous Ones.
Heenan was signed by the WWF in 1984 with the intention of him managing Jesse Ventura, however Ventura's retirement due to blood clots in his lungs prevented this from happening. Instead, Heenan managed Big John Studd in his feud against André the Giant. Studd challenged André to a US$15,000 bodyslam match at the first WrestleMania, with the stipulation being that André would have to retire had he lost. André won the match and then took the bag with the $15,000 and started throwing it out to the crowd before Heenan snatched the bag.
Heenan then reformed the Heenan Family, which over the years in the WWF would include Studd, "Olympic Strong Man" Ken Patera, "Playboy" Buddy Rose, "Mr. Wonderful" Paul Orndorff, King Kong Bundy, André the Giant, High Chief Siva Afi, the Brain Busters (Arn Anderson and Tully Blanchard), "Ravishing" Rick Rude, "King" Harley Race, the Islanders (Haku and Tama), Hercules, The Barbarian, Mr. Perfect, The Red Rooster, and The Brooklyn Brawler. Heenan and the Heenan Family had a feud with Hulk Hogan in the 1980s, and Heenan managed two WrestleMania challengers to Hogan's title. In 1986, Heenan managed King Kong Bundy in his main event bout at WrestleMania II. During the André the Giant–Hulk Hogan rivalry preceding WrestleMania III, André sided with Heenan and challenged Hogan at the event. While neither Bundy nor André won the title at that time, André later bested Hogan for the championship on The Main Event on February 5, 1988, in a controversial win after he aligned himself with "The Million Dollar Man" Ted DiBiase.
After being derided by announcers for his first five years in the WWF (mostly by Gorilla Monsoon) for never managing a champion, WrestleMania V was promoted (mostly by Jesse Ventura and later Gorilla Monsoon) as Heenan's quest, and best chance since WrestleMania III to manage a champion. Heenan finally managed his first champion in the WWF when "Ravishing" Rick Rude upset The Ultimate Warrior for the WWF Intercontinental Championship, a match Heenan insured Rude would win by holding Warrior's leg down so he could not break the pin. Shortly thereafter, he led the Brain Busters to win the WWF World Tag Team Championship. After the Busters had lost the titles back to Demolition a few months later, he led the Colossal Connection (André and Haku) to win the Tag Team Championship when they defeated Demolition. Demolition would win the titles back in WrestleMania VI. Immediately after the loss, Heenan began blaming the loss to André the Giant going as far as slapping him. A few months after that, he led Mr. Perfect to Intercontinental Championship success.
Heenan also wrestled sporadically in his WWF run. In his in-ring debut at Madison Square Garden in November 1984, he pinned Salvatore Bellomo. Heenan's most notable victory came at WrestleMania IV, teaming with The Islanders to defeat The British Bulldogs and Koko B. Ware. The following year, he was defeated in 30 seconds by former client The Red Rooster at WrestleMania V. Heenan also wrestled a series of "Weasel Suit matches" against The Ultimate Warrior, who defeated Heenan by forcing him into a weasel costume. His final in ring match came on February 16, 1991 at a house show in Long Island, NY, where he was defeated by The Big Boss Man.
Heenan retired from managing in 1991 to become a full-time commentator. Nonetheless, Heenan crossed the line to managing sporadically. When the WWF signed Ric Flair, Heenan spent several weeks talking Flair up as "The Real World's Heavyweight Champion", appearing onscreen with Flair's Big Gold Belt. He continued to act as an adviser to Flair during his WWF run from 1991 to 1993. Though he nominally managed Flair, Heenan's former protégé Mr. Perfect, who temporarily retired due to injury, would regularly accompany Flair to ringside as his "Executive Consultant". At the 1993 Royal Rumble, he introduced "The Narcissist" Lex Luger to the WWF to exact revenge on his former protégé, Mr. Perfect.
In 1984, WWF owner Vince McMahon took full advantage of his microphone and comedic skills and Heenan became a color commentator in addition to his managing duties. He replaced Jesse Ventura on Prime Time Wrestling and All American Wrestling, aired on the USA Network, teaming up with Gorilla Monsoon. He also replaced Ventura to team up with Monsoon on the syndicated All-Star Wrestling, which was replaced in the fall of 1986 with Wrestling Challenge. Although the purpose of these shows were to summarize weekly WWF events, viewers tuned in to see Heenan and Monsoon's interactions. Heenan, calling himself a "broadcast journalist", bashed fan favorites and cheered for their opponents while they cheated or did something under-handed. He referred to the fans as "humanoids", and fan favorites, especially enhancement talent, as "ham-and-eggers." Another moment between the pair often occurred when Heenan would go on a long rant supporting the villainous wrestlers, until an exasperated Monsoon would say either: "Will you stop?", "Give me a break!", or a sarcastic, "Please!"
Heenan, still suffering from the broken neck he received ten years earlier and unable to cope with the long working hours, decided to leave the WWF at the end of 1993. He was given an on-air farewell by Gorilla Monsoon on the edition of December 6, 1993 of Monday Night Raw, broadcast from the Westchester County Center in White Plains, New York. Fed up by Heenan's constant insults, Monsoon threw him and his belongings out of the arena and onto the street.
On January 27, 1994, Heenan made his debut in World Championship Wrestling (WCW). He was originally brought in to replace Jesse Ventura, his former client, as the color commentator for WCW Saturday Night and eventually took over Ventura's position as the company's lead commentator, replacing him for pay-per-view events and on the syndicated WCW WorldWide and Clash of the Champions events produced for TBS. When WCW Monday Nitro premiered in September 1995, Heenan left Saturday Night to work on the new show full-time and joined Steve McMichael as an analyst alongside play-by-play man Eric Bischoff. He was later frequently paired with Tony Schiavone.
In 1996, Heenan made a one-off return to ringside at The Great American Bash as the manager of two of his former clients, Ric Flair and Arn Anderson, in a tag team match against his broadcast colleague McMichael and Kevin Greene. Heenan was instrumental in convincing McMichael to turn on his partner, which enabled Flair and Anderson to win the match, and fill the open spot in The Four Horsemen that Brian Pillman left behind when he departed the company earlier in the year.
At the following pay-per-view, Bash at the Beach 1996, Heenan reacted incredulously when Hulk Hogan walked out during the main event match between The Outsiders (Kevin Nash and Scott Hall) and Sting, Lex Luger and Randy Savage by shouting "Whose side is he on?" Hogan subsequently turned his back on the fans and joined Hall and Nash to form the New World Order (nWo). Despite no longer being a fan favorite, Heenan continued to bash Hogan on commentary by gloating that he had been right about him all along, continuing a rivalry that dated back to their time in AWA.
Starting in late January 2000, WCW replaced Heenan on Monday Nitro and pay-per-view events with Mark Madden. Heenan continued to commentate on Thunder along with Mike Tenay, and later Schiavone, until he was replaced by Stevie Ray beginning in July 2000. Heenan was then only seen with Scott Hudson on Worldwide until he was released by WCW in November 2000.
On April 1, 2001, Heenan returned to the WWF and provided commentary to the Gimmick Battle Royal match at WrestleMania X-Seven alongside "Mean" Gene Okerlund. Heenan was inducted into the WWE Hall of Fame class of 2004 (WWF changed its name to WWE in 2002) by Blackjack Lanza. The following night, he appeared at WrestleMania XX in a skit with Gene Okerlund, Mae Young and The Fabulous Moolah. He inducted his protégés Paul Orndorff, The Blackjacks and Nick Bockwinkel into the WWE Hall of Fame class of 2005, class of 2006 and class of 2007 respectively. In his last WWE appearance, he was one of the speakers for "Mr McMahon Appreciation Night" on the June 11, 2007 episode of Raw.
On September 17, 2017, Heenan passed away.