Wepner, nicknamed "The Bayonne Bleeder," debuted as a professional boxer in 1964 and began posting many wins and some losses. He had formerly boxed while a member of the United States Marine Corps, and had worked as a security guard before turning pro. He was the New Jersey State Heavyweight Boxing Champion and popular fighter in the Northeast's Club Boxing circuit. But after losing fights to George Foreman (by knockout in three) and Sonny Liston (by knockout in ten) many boxing fans thought that his days as a contender were numbered. After the fight with Liston, Wepner needed over 120 sutures in his face. He also lost a fight to Jose King Roman by a decision in Puerto Rico.
However, after losing to Joe Bugner by a knockout in three in England, Wepner won nine of his next eleven fights, including victories over Charlie Polite and former WBA Heavyweight champion Ernie Terrell.
Then, in 1975, it was announced Wepner would challenge Muhammad Ali for the world's Heavyweight title. According to a Time magazine article, "In Stitches", Ali was guaranteed $1.5 million and Wepner signed for $100,000. This was considerably more than Wepner had ever earned and he therefore did not need any coaxing. Wepner spent eight weeks near the Catskill Mountains under the guidance of Al Braverman (manager) and Bill Prezant (trainer and noted cutman). Prezant prophesied that the fight would be a big surprise. This bout was the first time Wepner had been able to train full time. The fight was held on March 24 at the Richfield Coliseum in Richfield, Ohio south of Cleveland. Before the fight, a reporter asked Wepner if he thought he could survive in the ring with the champion, to which Wepner allegedly answered, "I've been a survivor my whole life...if I survived the Marines, I can survive Ali."
In the ninth round Wepner knocked down Ali, though Ali later contended that Wepner had stepped on his foot. Wepner went to his corner and said to his manager, "Al, start the car. We're going to the bank. We are millionaires." To which Wepner's manager replied, "You better turn around. He's getting up and he looks pissed off."
In the remaining rounds, Ali decisively outboxed Wepner and opened up cuts above both Wepner's eyes and broke his nose. Wepner was far behind on the scorecards when Ali knocked him down with 19 seconds left in the 15th round. The referee counted to nine before calling a technical knockout. It is rumored that Young actor Sylvester Stallone watched the fight at home on television and was inspired to write the script for Rocky, based on Wepner's gutsy challenge, but Stallone subsequently denied that this was true. Wepner filed a law suit which was eventually settled with Stallone for an undisclosed amount.
In 1976, Wepner fought professional wrestler André the Giant and lost by countout after Andre threw him out of the ring. It is speculated that the 1982 film Rocky III was influenced by this fight, as the movie features a match versus wrestler Hulk Hogan as "Thunderlips", who throws Rocky out of the ring.