A man named Leonard Shelby suffers from short-term memory loss resulting from an injury incurred during the attack on his wife, which also left her murdered. Unable to form new memories, he can only retain information for a few minutes. Driven by a desire to find his wife's killer, Leonard uses a complex system of notes, Polaroid photographs, and tattoos with vital information to track progress and clues. His condition makes him vulnerable and easily manipulated, yet he's determined to uncover the truth, relying on his own structured system of memory substitutes to compensate for his impairment.

Leonard's story unfolds in two separate sequences of scenes: a series of black-and-white scenes shown in chronological order, and a series of color scenes shown in reverse order. The black-and-white scenes take place in various motel rooms, where Leonard speaks on the phone, providing background information about his condition, his life before the incident, and his drive for vengeance. In the color sequences, Leonard interacts with a few key characters including a bartender named Natalie, who may have her own hidden agenda, and Teddy, a man who claims to be Leonard's friend while appearing to have his own mysterious motives. As the two sequences of scenes interweave, a complex narrative emerges, challenging the viewers to piece together a puzzle that mirrors Leonard's fragmented and unreliable perspective.