He became the youngest boxer to take the title from a reigning heavyweight champion at the age of 22

By late 1963, Clay (his birth name) had established himself as the leading contender for Sonny Liston's belt. The battle was scheduled to take place on February 25, 1964, in Miami Beach. Liston had an intimidating attitude and was a dominant fighter with a criminal background and ties to the mob. Clay was a 7–1 underdog based on his uninspiring performance against Jones and Cooper in his previous two fights, and Liston's annihilation of former heavyweight champion Floyd Patterson in two first-round knockouts.

The fight resulted in a stunning upset. At the start of the fight, Liston charged at Clay, seemingly angry and looking for a quick knockout. Clay's better speed and agility, on the other hand, allowed him to avoid Liston, causing the champion to miss and appear awkward. At the close of the first round, Clay opened up his offensive and repeatedly jabbed Liston. Liston fought better in round two, but Clay caught him with a combination that collapsed his knees and created a cut beneath his left eye in the third round. This was the first time Liston had ever been cut. Clay was returning to his corner at the end of round four when he began to experience blinding pain in his eyes and requested his trainer, Angelo Dundee, to cut off his gloves.

Despite Liston's attempts to knock out a blinded Clay, Clay managed to make it through the fifth round until perspiration and tears washed the irritation from his eyes. Clay dominated the sixth, regularly striking Liston. Liston did not respond to the seventh-round bell, and Clay was proclaimed the winner by TKO. He became the youngest boxer to take the title from a reigning heavyweight champion at the age of 22.