Clarice Starling is a young trainer agent with the F.B.I. when she is summoned to a meeting with the head of the Behavioral Science Unit at Quantico. She is given an unexpected job to do; she must go to the secure prison where infamous serial murderer Hannibal "The Cannibal" Lecter is held and interview him about the identity of a serial killer currently murdering women and believed to be a follower of Dr Lecter. The unidentifiable killer has been nicknamed Buffalo Bill. His specialty is skinning the women he kills.
When they meet, Dr Lecter, a brilliant psychiatrist, is impressed with Clarice's analysis of Buffalo Bill. This fades, however, when she hands him the standardized FBI psychological questionnaire that he feels is insulting to his intelligence. He tells her to leave but as she does so, another prisoner makes threatening sexual comments and Dr Lecter decides to help Clarice find Buffalo Bill - to a degree. His assistance is never straightforward but consists of cryptic clues and throwaway remarks. The first remark leads Clarice to a storage unit that seems abandoned. Inside the unit is the severed head of one of Dr Lecter's one-time patients, but Lecter insists that he did not kill this man - Buffalo Bill did. This is a revelation because it is a guarded admission that he knows Buffalo Bill's true identity. This information is his bargaining chip; he will reveal the killer's identity to Clarice but only after she had arranged for him to be transferred to another facility, he doesn't mind where, just as long as he is no longer under the treatment of the prison's psychiatrist Dr Chilton.
Time is pressing. Another young woman is kidnapped. Another body is found floating in the river. At the autopsy Clarice is shown the woman's body which has been sickeningly mutilated. There are diamond-shaped holes in her back where flesh has been removed and there is an insect cocoon stuck in the throat. The insect turns out to be a death head moth.
All serial killers have a pattern or a signature that is discernible each time they kill. Buffalo Bill is no different. He kills the women he kidnaps within three days of taking them. Mindful of this Clarice makes a fake offer to Dr Lecter that promises the transfer he wants. Unfortunately Dr Chilton is working against her, fixated more on getting the information out of Lecter (and therefore the credit for doing so) all to himself. He tells Hannibal that Clarice's offer is fake and makes his own offer instead; transfer to Memphis and a meeting with Senator Martin, kidnap victim Catherine Martin's mother. Buffalo Bill is keeping Catherine alive, and has her imprisoned in a pit beneath his house, forcing her to apply moisturizer to her body to keep her skin soft and supple. It is easier for him to remove that way.
Dr Lecter tells Clarice to look for a man called Louis Friend. Clarice realized the name is a fake one, an anagram of the name of Buffalo Bill, but she has no way to decipher the conundrum. She wants more information but the doctor is manipulative and psychotic and wants information from Clarice; personal information, trading an answer to one of his questions in return for answering one of hers. She tells him that she grew up on a farm, that she was an orphan, that the sound of lambs being slaughtered in the barn would keep her awake at night. Clarice's meeting is not officially authorized and she is asked to leave. After she does so, Lecter escapes by picking the lock on his handcuffs with a pen that he stole unseen from Dr Chilton. He kills two prison guards and escapes.
Clarice, unaware of his escape, ploughs on with her investigation and decides to look at the first murder again. She discovers a dress that has diamond shapes cut out of the back, and also some photographs. She contacts a person that the victim used to work for and when Buffalo Bill invites her into the house to try to find out how close they are to identifying the killer, she spies a moth with a skull shape on its back. She realizes that the man she is speaking to is Buffalo Bill. She chases him through the house and they end up in the dark basement space ultimately rescuing Catherine Martin.
Clarice graduates from the FBI academy top of her class, receiving a call from Dr Lecter congratulating her. He does not tell her where he is.
