Mo' Better Blues is a drama that is taking place in Brooklyn, New York. In the beginning of the film a group of friends come to Bleek's house to ask if he can come out and play. Bleek is not allowed to come out and play with the boys; Bleek has to continue practicing the trumpet. There is a struggle between parents because Bleek's father does not approve of his son practicing the trumpet all the time. In the mean time Bleek's mother is avid that he learns to play the trumpet correctly.
The film is then fast forwarded as an adult Bleek playing at a jazz club with his band. His childhood friend Giant is now his manager. Bleek's girlfriend is Indigo Downes, but he is also dating another woman Clarke Bentancourt. Clarke is a signer, and she wants to get in the action. She makes a suggestion to Bleek that she sings in his band, but Bleek tells Clarke no.
In the meantime Giant has a gambling problem and is in debt. The band is making a lot of money, but Giant is uses some of the money to keep up with his gambling problem. He finds himself in a situation where he is unable to repay his debt. Giant is fired as the band's manager. Bleek helps Giant the best he can and lets Giant stay with him.
Clarke has moved on and started dating one of the band's member Shadow. Bleek has to let Shadow go. Bleek tries his best to get the money to help Giant, but Giant is confronted by his debtors and his beaten. Bleek tries to stop the fight, and he is struck in his mouth with his own trumpet. Bleek's lips are injured. He is permanently unable to play the trumpet.
Time passes by and Bleek reunites with Giant who is no longer gambling, and Bleek reunites with Clarke who is singing with Shadow and his former band. Bleek is unable to play correctly. He leaves and goes back to his ex-girlfriend Indigo. Indigo is furious it has been a year since she saw Bleek. However they are reunited and get married. The two also have a son Miles. The film ends with Bleek teaching Miles how to play the trumpet.