Clarice Starling, an FBI trainee, is assigned by her boss, Jack Crawford, to interview the incarcerated Hannibal Lecter, a highly intelligent former psychiatrist and cannibalistic serial killer. Crawford secretly hopes to gain insights into a psychopathic serial killer known as "Buffalo Bill", who kills overweight women and skins them.
Starling meets Lecter in his cell at the Baltimore State Hospital for the Criminally Insane. Although initially courteous, Lecter rebuffs her, deducing Crawford's true motive. As she is leaving, another prisoner, Miggs, flings his semen at her, angering Lecter, who changes his mind and provides Starling a clue. The clue leads to a jar holding a man's severed head. The man is linked to Buffalo Bill, and Lecter offers to profile the killer on the condition that he is transferred away from Dr. Frederick Chilton, whom he detests. Meanwhile, Lecter influences Miggs into swallowing his own tongue and committing suicide, presumably to avenge his revolting action toward Starling, and another victim is found, with a death's head moth lodged in her throat.
In Tennessee, Buffalo Bill abducts Catherine Martin, the daughter of a U.S. senator. Crawford authorizes Starling to offer Lecter a fake deal, promising a prison transfer if he helps them capture Buffalo Bill in time to rescue Catherine. Instead, Lecter demands a quid pro quo, offering clues in exchange for personal information about Starling; she agrees. Chilton exposes Starling's deceit and offers Lecter a new deal. Lecter agrees and is flown to Memphis, where he gives Senator Martin accurate information on Buffalo Bill's appearance but falsely identifies him as "Louis Friend".
Starling figures out the name is an anagram of "iron sulfide", also known as "fool's gold". She visits Lecter, now imprisoned in Tennessee. She describes a traumatic childhood incident wherein she heard lambs screaming at slaughter in the barn but could not save them. Lecter speculates that she hopes saving Catherine will end the recurring nightmares she has from this event. Satisfied, he returns the case files to her. That evening, Lecter brutally kills his two guards and escapes from his cell.
With her notes from Lecter, Starling figures out that Buffalo Bill knew his first victim: Frederika Bimmel. She travels to Bimmel's Ohio hometown and discovers that she and Buffalo Bill were both tailors. In Bimmel's room, she finds evidence that reveals Buffalo Bill is making a suit with human skin. The culprit is a man named Jame Gumb, who believes he is transsexual but was deemed too violent to apply for a sex-change operation. Crawford and an FBI Hostage Rescue Team storm Gumb's address in Illinois but find the house empty. Meanwhile, Starling follows a lead that takes her to the house of Bimmel's former client. There, she meets the real Jame Gumb, realizing he is Buffalo Bill after spotting a death's head moth. She pursues him and finds Catherine trapped in a dry well in the cavernous basement. Gumb stalks Starling with night-vision goggles but reveals himself by cocking his revolver; she reacts quickly and shoots him dead.
At the FBI Academy graduation party, Starling receives a phone call from Lecter, who is in the Bahamas at a Bimini airport. He assures her that he has no intention of pursuing her and requests that she return the favor, which she says she cannot. He hangs up, stating that he is "having an old friend for dinner" as he trails a newly arrived Chilton into the crowd.
