As heavyweight champion, Holmes won his first 48 professional challenge fights, falling just one short of matching Rocky Marciano's record of 49 consecutive wins to start a career.

Holmes was born in Cuthbert, Georgia, but he has spent the majority of his life living in Easton, Pennsylvania, from which he gained his boxing nickname, "The Easton Assassin."

In October 1980, Muhammad Ali came out of retirement to face Holmes. Ali was a shadow of his former self, and Holmes dominated the fight. Ali's trainer, Angelo Dundee, stopped the fight after the tenth round. Holmes successfully defended the WBC belt 17 times until December 11, 1983, when he voluntarily relinquished that title for the championship of the new International Boxing Federation. Many fans attribute the IBF's early survival to Holmes' involvement as its first heavyweight champion.

By the time he had his first loss to Michael Spinks, he was almost 36 years old. Holmes' lack of popularity is attributed to him being the direct successor to Muhammad Ali, one of the most accomplished and most loved heavyweight champions of all time.

Holmes is regarded as having one of, if not the, greatest left jabs in heavyweight boxing history.