College student Jeffrey Beaumont (Kyle MacLachlan) returns home after his father has a stroke. When he discovers a severed ear in an abandoned field, Beaumont teams up with detective’s daughter Sandy Williams (Laura Dern) to solve the mystery. They believe beautiful lounge singer Dorothy Vallens (Isabella Rossellini) may be connected with the case, and Beaumont finds himself becoming drawn into her dark, twisted world, where he encounters sexually depraved psychopath Frank Booth (Dennis Hopper).
FBI criminal profiler Will Graham (William L. Petersen) is called out of early retirement to assist on a serial murder case involving a killer known as the “Tooth Fairy” (Tom Noonan). Graham enlists the help of imprisoned serial killer — and cannibal — Dr. Hannibal Lecktor (Brian Cox), who is the reason Graham took early retirement. Soon, Graham and the FBI are entangled in a deadly cat-and-mouse game between the Tooth Fairy, Lecktor, and an interfering journalist (Stephen Lang).