In 1928 Baltimore, Eleanora Fagan, also known as Billie Holiday, works as a 15-year-old housekeeper in a brothel. A man who follows her from the brothel eventually rapes her. She flees to her mother Sadie, who sets her up a job cleaning for another brothel in Harlem. The brothel is run by Lorraine, a woman who pays little money to Billie. Billie tires of scrubbing floors and becomes a prostitute, but soon quits and returns to a nightclub to unsuccessfully audition to become a showgirl. After Piano Man accompanies her on stage, the club owner Jerry books her as a singer in the show.
Billie's debut begins unsuccessfully, until Louis McKay arrives and gives her a twenty-dollar tip. Billie soon begins a relationship with Louis. Eventually, she is discovered by bandleaders Harry and Reg Hanley, who sign her as a soloist for their southern tour in hopes of landing a radio network gig. During the tour, Billie witnesses the aftermath of the lynching of an African-American man, which presses her to record a song. The harsh experiences on the tour result in Billie taking drugs, which he supplies after she collapses on stage. One night, when Billie is performing, Louis comes to see her. After realizing that Billie is doing drugs, Louis says that she is going home with him.
In New York, Reg and Louis arrange for Billie's radio debut, but the station does not call her up to the stage to sing; the radio sponsor, a soap company, objected to her race. Disappointed, the group heads to Cafe Manhattan. There, Billie gets drunk and asks Harry for drugs. Angered, Billie is ready to leave, but Louis arranged for her to sing at the Cafe, a club where she once aspired to sing. She obliges with one song but refuses an encore, leaving in need of a fix. Louis, suspicious that Billie broke her promise, takes her back to his home but refuses to allow her access to the bathroom or her kit. She fights Louis for it, pulling a razor on him. Louis leaves her to shoot up, saying that he does not want her there when he returns.
Billie returns to the Harlem nightclub, where her drug use intensifies until she hears of Sadie's death. Billie checks herself into a drug clinic, but cannot afford her treatment there. The doctor secretly calls Louis, who starts paying her bills without her knowledge. Impressed with the initiative that she has taken to straighten herself out, Louis proposes to her at the hospital.
Billie is soon arrested for possession of narcotics and removed from the clinic. In prison, she goes through withdrawal. Louis brings the doctor from the hospital to treat her, but she is incoherent. He puts a ring on her finger to remind Billie of his promise to marry her. After finishing her sentence, Billie returns home and does not want to sing anymore.
Billie marries Louis and pledges not to continue her career. She, however, eventually returns to singing, with Louis as her manager. However, her felony conviction stripped Billie of her Cabaret Card, which would allow her to sing in New York nightclubs. To restore public confidence and regain her license, Billie agrees to a cross-country tour. Her career takes off on the nightclub circuit.
Louis leaves for New York to arrange for a comeback performance for Billie at Carnegie Hall. Despondent at Louis's absence and the constant stream of venues, Billie asks Piano Man to pawn the ring that Louis gave her in exchange for drugs. While they are high that evening, his drug connections arrive; he neither pawned the ring nor paid for the drugs. The dealers kill Piano Man. Within the hour, Louis and her promoter call Billie with news that they completed the Carnegie Hall deal. Louis returns to find a traumatized Billie, who has fallen back into drugs.
Billie plays at Carnegie Hall, but never succeeds in swaying the commission to restore her license. Billie is eventually re-arrested on drug charges and dies at age 44.
