Sara Goldfarb, a widow who lives alone in a Brighton Beach apartment, spends her time watching television. Her son Harry is a heroin addict, along with his friend Tyrone and girlfriend Marion. The three traffic heroin in a bid to realize their dreams; Harry and Marion plan to open a clothing store for Marion’s designs, while Tyrone seeks escape from the ghetto and the approval of his mother. When Sara receives a call that she has been invited to her favorite game show, she begins a restrictive crash diet in an attempt to fit into a red dress that she wore at Harry’s graduation.
At the recommendation of a friend, she visits a physician who prescribes her amphetamines to control her appetite. She begins losing weight rapidly and is excited by how much energy she has. When Harry recognizes the signs and persuades her to stop taking the amphetamines, Sara insists that the chance to appear on television and the increased admiration from her friends are her remaining reasons to live. Sara becomes frantic waiting for the invitation and increases her dosage, which causes her to develop amphetamine psychosis.
Tyrone is caught in a shootout between black traffickers and the Sicilian Mafia, and is arrested despite his innocence. Harry has to use most of their earned money to post bail. The local supply of heroin becomes restricted, and they are unable to find any to buy. Eventually, Tyrone hears of a large shipment coming to New York from Florida, but the price is doubled and the minimum high. Harry encourages Marion to engage in prostitution with her psychiatrist, Arnold, for money. This request, along with their mounting withdrawal, strains their relationship.
Sara’s increased dosage distorts her sense of reality and begins to hallucinate, in which she is mocked by the host and crowd from the television show and attacked by her refrigerator. Sara flees her apartment and goes to the casting agency office in Manhattan to confirm when she will be on television. Sara’s disturbed state causes her to be admitted to a psychiatric ward, where she fails to respond to various medications. She undergoes electroconvulsive therapy instead. Harry and Tyrone travel to Miami to buy directly from the wholesaler. However, they are forced to stop at a hospital because of Harry’s gangrenous arm. The shocked doctor realizes Harry and Tyrone’s situation and they are arrested.
Back in New York, a desperate Marion sells her body to a pimp, Big Tim, in exchange for heroin, and receives even more when she subjects herself to a humiliating sex show at his request. Sara’s treatment leaves her in a dissociated and vegetative state, to the horror of her friends. Harry’s arm is amputated and he is emotionally distraught by the knowledge that Marion will not visit him. Marion returns home from the show and lies on her sofa, clutching her score of heroin and surrounded by her crumpled and discarded clothing designs. Tyrone is taunted by racist prison guards while enduring a combination of manual labor and withdrawal symptoms. Each of the four characters curl into a fetal position. Sara imagines herself as the beautiful winner of the game show, with Harry—married and successful—arriving as a guest. Sara and Harry lovingly embrace.