The film begins with Cassius Clay Jr. before his championship debut against then-heavyweight champion Sonny Liston. Clay taunts Liston, then dominates the early rounds of the match. Halfway through, he complains of a burning feeling in his eyes (implying that Liston has tried to cheat) and says he is unable to continue. However, his trainer/manager Angelo Dundee gets him to keep fighting. Once Clay is able to see again, he dominates the fight and Liston quits before round seven, making Clay the second-youngest heavyweight champion at the time after Floyd Patterson.
Clay spends time with Malcolm X, then is invited to the home of Nation of Islam leader Elijah Muhammad, where he is granted the name Muhammad Ali. His father, Cassius Clay Sr. disapproves of this. Ali marries Sonji Roi, an ex-Playboy Bunny, although she is not Muslim and does not abide sex segregation. Ali goes to Africa and meets up with Malcolm X, but later refuses to speak to him, honoring the wishes of Elijah Muhammad. He is extremely distraught when X is later assassinated.
Upon returning to America, Ali goes against Sonny Liston a second time and knocks him out in the first round. He and Sonji divorce after she objects to various obligations Muslim women have.
Ali refuses conscription for the Vietnam War and is stripped of his boxing license, passport and title, and sentenced to five years in prison. Ali marries 17-year-old Belinda Boyd. After a three-year hiatus, his conviction is overturned and in his comeback fight, he goes against Jerry Quarry and wins by technical knockout in three rounds.
Ali attempts to regain the heavyweight championship against Joe Frazier. In the “Fight of the Century”, Frazier generally has the upper hand against Ali and wins by decision, the first loss of Ali’s career. Frazier later loses the championship to George Foreman.
Foreman and Ali go to Kinshasa, Zaire, for the Rumble in the Jungle fight. There Ali meets Veronica Porché and has an affair with her. After reading rumors of his infidelity through newspapers, his wife Belinda travels to Zaire to confront him about this. Ali says he is unsure as to whether he really loves Veronica or not, and just wants to focus on his upcoming title shot.
For a good portion of the fight against Foreman, Ali leans back against the ropes, allowing Foreman to tire himself out. Then he knocks out the tired Foreman, regaining the Heavyweight Championship.