Holmes, a street fighter in his youth, entered organized boxing at a youth centre in Easton, Pennsylvania. He won 19 of his 22 fights and several titles before turning professional at age 24. In the mid-1970s he was a sparring partner for both competing heavyweight champions, Muhammad Ali (Ali, Muhammad) and Joe Frazier (Frazier, Joe). Holmes struggled to establish his identity as a first-rate fighter with these two great heavyweights in contention and found it difficult to get top-level bouts.

From 1973 to 1978 Holmes won 28 consecutive bouts, culminating in a victorious 15-round decision over reigning champion Ken Norton on June 9, 1978, for the World Boxing Council (WBC) heavyweight crown. Holmes defended the title 17 times between 1978 and 1983, defeating such formidable boxers as Earnie Shavers, Leon Spinks (Spinks, Leon), and Gerry Cooney. On October 2, 1980, Holmes faced the celebrated Ali, who at age 38 was mounting a comeback. Holmes won in 11 rounds, cementing his claim as world heavyweight champion. The fight, however, was emotionally difficult for Holmes. He counted Ali as a good friend, and this fight, occurring after Ali's prime, put Holmes in the position of having to beat, in fact pummel, his mentor.

In 1983, amid ongoing disagreements with boxing promoter Don King (King, Don), Holmes relinquished his WBC title. The International Boxing Federation, however, still regarded him as heavyweight champion, and he defended that title three times before losing it to Michael Spinks (Spinks, Leon) in a 15-round decision on September 21, 1985. Holmes retired after the loss, his first in 49 bouts, which kept him from matching Rocky Marciano (Marciano, Rocky)'s career record of 49–0.

Holmes came out of retirement in 1986, only to lose a rematch to Michael Spinks. In 1988 he again returned to the ring to take on heavyweight champion Mike Tyson (Tyson, Mike); the referee halted the fight in the fourth round after Holmes had endured three early knockdowns. In 1991, after beating opponent Ray Mercer, Holmes advanced to the title bout with Evander Holyfield (Holyfield, Evander), who defeated him in a decision. On April 8, 1995, Holmes challenged Oliver McCall for the WBC heavyweight crown but lost in 12 rounds.