Jack Crawford, head of the Behavioral Science Unit at the FBI, sends Clarice Starling, an agent in training, to meet with Hannibal “The Cannibal” Lecter. Lecter is a renowned psychiatrist turned serial killer. Crawford wants Starling to get Lecter to complete a questionnaire regarding his psychological profile. In reality, Crawford hopes Starling will get information from Lecter regarding Buffalo Bill, an active serial killer who skins his victims. Starling meets with Lecter at the Baltimore Hospital for the Criminally Insane. Lecter immediately realizes why Crawford sent Starling, and after picking her apart psychologically, he gives her a vague lead to help with the Buffalo Bill case: he advises her to “look in Raspail’s car.”
Starling takes Lecter’s advice and visits a storage unit owned by Benjamin Raspail, who was one of Lecter’s patients before Lecter murdered him. In the unit, she finds a severed head, though she does not know who it belongs to or what it has to do with the Buffalo Bill case. Starling repeatedly returns to Lecter for more information. He tells her that the severed head belongs to Raspail’s former lover—during one of his therapy sessions with Lecter, Raspail confessed to killing him. Lecter also repeatedly implies that he knows who Buffalo Bill is, though he does not share his information with Starling. Instead, he asks Starling personal questions about herself. The more Starling tells Lecter, the more he shares with her.
While Starling pursues the case, Buffalo Bill—who, unbeknownst to the FBI, is a man named Jame Gumb—kidnaps Catherine Baker Martin, the daughter of a United States Senator. Because Catherine Baker Martin is a high-profile person, the FBI faces more pressure and scrutiny than ever to solve the case quickly. So, Crawford sends Starling to Lecter with a fake deal: if Lecter helps them capture Buffalo Bill before he can kill Catherine Baker Martin, he will get transferred to a better facility where he will have more freedom. At this point, Lecter reveals more information than before, though he still does not give Starling a name. He tells Starling that Buffalo Bill is killing women because he thinks he is transsexual, and he wants to make a body suit for himself out of women’s skin. But Lecter clarifies that he is not truly transsexual; this is just one of many ways Buffalo Bill has tried to transform himself throughout his life.
After Starling leaves, Dr. Chilton, who oversees Lecter, tells him that Starling’s deal was fake. However, Chilton is in contact with Senator Ruth Martin, Catherine's mother, and promises to get Lecter a real deal if he cooperates. Chilton takes Lecter to Tennessee, where they meet with Senator Martin. Lecter gives the Senator what he claims is Buffalo Bill’s real name, but he lies.
Around the same time, Starling is also in Tennessee pursuing a lead. However, her superiors at the Department of Justice take her off the case. Before returning home, Starling goes to the Memphis Courthouse, where the Tennessee authorities are holding Lecter in a cage. She lies her way into the building and speaks to Lecter one final time. Lecter asks Starling for information about herself in return for information about the case. Starling tells Lecter about one of her childhood memories. After her father’s death, Starling went to live with her relatives on a ranch. She became close with the animals and was horrified when she learned her relatives slaughtered them as part of their business. Starling woke one night to the sound of lambs crying as her relatives slaughtered them. Starling still hears that sound in her dreams. Before she can get answers from Lecter, Chilton arrives and takes her away from him. However, before she goes, Lecter hands her back her case file, which he had been looking over.
After Starling leaves Tennessee, Lecter breaks out of his cage by murdering the police officers looking after him. He poses as one of the officers by using a pocket knife to carve one of their faces off and place it on his own; he also changes into the man’s clothes. Then, he calls an ambulance for himself and gets carried out by EMTs. By the time the authorities realize what has happened, Lecter has killed the EMTs and is nowhere to be found.
Following Lecter’s escape, Crawford finally gets a breakthrough in the Buffalo Bill case that sends him and his team to an address in Illinois. Meanwhile, Starling travels to Ohio to look at one of the old Buffalo Bill crime scenes, hoping that she will find something to help her find the case. Crawford’s lead ends up being a bust. However, as Starling interviews people around town, she unwittingly finds herself in Jame Gumb’s home, where he is holding Catherine. At first, Starling does not recognize Jame Gumb as the suspect she’s looking for. However, while in Gumb’s house, she spots a rare Death’s Head Moth in the house. Suddenly, she realizes she is speaking to Buffalo Bill because the killer shoves the cocoons of this exotic moth into his victims’ throats. Starling tries to arrest Gumb, but he runs down into his basement. Starling chases after Gumb, and she eventually shoots and kills him. Luckily, Catherine is still alive, and Starling saves her from the pit Gumb was holding her in.
Following Gumb’s death, the FBI scours his basement and discovers several bodies they did not know about. Starling discovers that Lecter knew about Gumb because he was friends with Raspail. Gumb is also the one who actually killed Raspail’s lover, Klaus, whose head Starling found in Raspail’s storage unit.
After the Buffalo Bill case is closed, Lecter sends Starling a letter. Although he does not say so to Starling, he has undergone a lot of plastic surgery and changed his identity. In his letter, Lecter asks Starling to have the newspapers publish something about whether the lambs from her dream have gone silent. Lecter suspects they have for the time being, but they will start up again eventually. Meanwhile, Starling sleeps soundly next to Pilcher, an entomologist she met while on the Buffalo Bill case, who she is now dating.
