It's 1964 and former Olympic boxing champion Cassius Clay, Jr. (WILL SMITH) is about to fight Sonny Liston (MICHAEL BENTT) for the heavyweight championship of the world. Known for both his physical and verbal prowess, Ali's supported by his corner team consisting of trainer Angelo Dundee (RON SILVER) and motivational guru Drew "Bundini" Brown (JAMIE FOXX).
With sports reporter Howard Cosell (JON VOIGHT) covering the fight, friend Howard Bingham (JEFFREY WRIGHT) taking photos of it, and Malcolm X (MARIO VAN PEEBLES) there lending support, the underdog prevails and becomes the champion.
Inspired by Malcolm X, Clay decides to join the Nation of Islam and is given the name Muhammad Ali by the religion's leader, Elijah Muhammad (ALBERT HALL). With his son, Herbert Muhammad (BARRY "SHABAKA" HENLEY), now serving as Ali's spiritual guide and manager, the boxer soon has a falling out with Malcolm X, but fills that void when he meets Sonji Roi (JADA PINKETT SMITH), who eventually becomes his first wife.
Time passes, Malcolm X is assassinated and the government starts watching Ali for fear of militant and/or verbal Black Muslims. Ali's clash with the government worsens when he refuses to be inducted into the U.S. Army to fight in Vietnam. Although supported by his friends and lawyer Chauncy Eskridge (JOE MORTON), the champ is stripped of his title and banned from fighting as his case moves its way up through the courts.
By this time, he's seeing Belinda (NONA GAYE), who becomes his second wife and watches as boxer Joe Frazier (JAMES TONEY) becomes the new heavyweight champ. With Ali's case eventually behind him, he then travels to Zaire where he meets yet another lover, Veronica Porsche (MICHAEL MICHELE), as he prepares to regain his title in a fight arranged by promoter Don King (MYKELTI WILLIAMSON) against the hulking George Foreman (CHARLES SHUFFORD).