In 1983, Clarice Starling, a young FBI trainee, is asked to carry out an errand by Jack Crawford, the head of the FBI division that draws up psychological profiles of serial killers. Starling is to present a questionnaire to brilliant forensic psychiatrist and cannibalistic sociopath, Hannibal Lecter. Lecter is serving nine consecutive life sentences in a Maryland mental institution for a series of murders.
Crawford's real intention, however, is to try and solicit Lecter's assistance in the hunt for a serial killer dubbed 'Buffalo Bill", whose modus operandi involves kidnapping overweight women, starving them for about three or four days, and then killing and skinning them, before dumping the bodies in nearby rivers. The nickname was started by Kansas City Homicide, as a joke that "he likes to skin his humps." Throughout the investigation, Starling periodically returns to Lecter in search of information, and the two form a strange relationship in which he offers her cryptic clues in return for information about her troubled and bleak childhood as an orphan.
When Bill's sixth victim is found in West Virginia, Starling helps Crawford perform the autopsy. Starling finds a moth pupa in the throat of the victim, and just as Lecter predicted, she has been scalped. Triangular patches of skin have also been taken from her shoulders. Furthermore, autopsy reports indicate that Bill killed her within four days of her capture, much faster than his earlier victims. On the basis of Lecter's prediction, Starling believes that he knows who Buffalo Bill really is. She also asks why she was sent to fish for information on Buffalo Bill without being told she was doing so; Crawford explains that if she had had an agenda, Lecter would never have spoken up.
Starling takes the pupa to the Smithsonian, where it is eventually identified as the Black Witch Moth, which would not naturally occur where the victim was found.
In Tennessee, Catherine Baker Martin, daughter of Senator Ruth Martin, is kidnaped. Within six hours, her blouse is found on the roadside, slit up the back: Buffalo Bill's calling card. Crawford is advised that no less than the President of the United States has expressed "intense interest" in the case and that a successful rescue is preferable. Crawford estimates they have three days before Catherine is killed. Starling is sent to Lecter with the offer of a deal: if he assists in Catherine's rescue and Buffalo Bill's capture, he will be transferred out of the asylum, something he was continually longed for. However, Lecter expresses skepticism at the genuineness of the offer.
After Starling leaves, Lecter reminisces on the past, recalling a conversation with Benjamin Raspail, a former patient whom he later murdered. Raspail, during that therapy session, explained the death of a sailor named Klaus at the hands of Raspail's jealous former lover, Jame Gumb, who then used Klaus' skin to make an apron. Raspail also revealed that Gumb had an epiphany upon watching a moth hatch. Lecter's ruminations are interrupted when Dr. Frederick Chilton - the asylum's administrator and Lecter's nemesis - steps in. A listening device allowed him to record Starling's offer, and Chilton has found out that Crawford's deal is a lie. He offers one of his own: If Lecter reveals Buffalo Bill's identity, he will indeed get a transfer to another asylum but only if Chilton gets credit for getting the information from him. Lecter insists that he'll only give the information to Senator Martin in person, in Tennessee. Chilton agrees. Unknown to Chilton, Lecter has previously hidden under his tongue a paperclip and some parts of a pen, both of which were mistakenly given to him by untrained orderlies over his many years at the asylum. He fashions the pen pieces and paperclip into an improvised lockpick, which he later uses to pick his handcuff locks.
In Tennessee, Lecter toys with Senator Martin briefly, enjoying the woman's anguish, but eventually gives her some information about Buffalo Bill: his name is William "Billy" Rubin, and he has suffered from elephant ivory anthrax, a knifemaker's disease. He also provides an accurate physical description. The name, however, is a red herring: bilirubin is a pigment in human bile and a chief coloring agent in human feces, which the forensic lab compares to the color of Chilton's hair.
Starling tries one last time to get information from Lecter as he is about to be transferred. He offers a final clue - "we covet what we see everyday" - and demands to hear her worst memory. Starling reveals that, after her father's death, she was sent to live with a cousin on a sheep ranch. One night, she discovered the farmer slaughtering the spring lambs and fled in terror. The farmer caught her and sent her to an orphanage, where she spent the rest of her childhood. Lecter thanks her, and the two share a brief moment of connection before Chilton forces her to leave. Later on, she deduces from Lecter's clue that Buffalo Bill knew his first victim.
Shortly after this, Lecter escapes by killing and eviscerating his guards, using one of their faces as a mask to fool paramedics. Starling continues her search for Buffalo Bill, eventually tracking him down and killing him and rescuing Catherine. She is made a full-fledged FBI agent, and receives a congratulatory telegram from Lecter, who hopes that "the lambs have stopped screaming".