The film takes place 10 years after the events depicted in The Silence of the Lambs. FBI Agent Clarice Starling (Julianne Moore) is disgraced after a botched drug raid resulting in the deaths of five people, including HIV-positive drug dealer Evelda Drumgo (Hazelle Goodman), who was shot by Starling while holding a baby—and threatening Starling with a “whispering death” (MAC-10). Though Starling had tried to abort the raid before a violent situation developed, another officer charged ahead and precipitated the gun battle with Drumgo and her bodyguards, and Starling is unjustly blamed for the bloodbath by Justice Department official Paul Krendler (Ray Liotta), whose romantic advances Starling had rejected years earlier.
As a result of the publicity surrounding the drug raid, Starling and her past connection to escaped cannibalistic serial killer Hannibal Lecter come to the attention of one of Lecter’s victims, Mason Verger (Gary Oldman), a wealthy, sadistic pedophile. Verger, who was left horrifically disfigured and paralyzed by his encounter with Lecter, still seeks revenge for what occurred. He uses his political influence to have Starling assigned to the Lecter case once again in the hope that this will draw Lecter out of hiding.
Verger claims to have new information about Lecter (an X-ray) which he is willing to disclose only to Starling, and she is sent to his estate to collect it and interview him. Upon her arrival, Verger tells Starling about his history with Lecter. They met when Lecter was assigned by a court as Verger’s therapist after Verger’s conviction on multiple counts of child molestation. Verger, the only one of Lecter’s victims to survive, is now bedridden and confined to his secluded mansion, but with the assistance of his personal physician Cordell (Željko Ivanek) and other minions he is pursuing an elaborate scheme to capture, torture and kill Lecter.
In Florence, Italy, Chief Inspector Rinaldo Pazzi of the Questura (Giancarlo Giannini) is investigating the disappearance of the curator of the Capponi Library, a Renaissance palace that serves as a repository of rare books, historical documents and art treasures. In the course of his investigation, Pazzi meets the new curator: “Dr. Fell,” who is actually Hannibal Lecter.
As Verger surmised, Lecter soon learns of Starling’s public disgrace and of her reassignment to his case, and sends her a letter that is at once sympathetic and mocking. The letter contains no apparent clue to Lecter’s whereabouts, but Starling detects a strange fragrance on it. She takes it to a perfume company, where the experts inform her that the writer used a skin cream that could have been made by only a few shops in the world, one of which is in Florence.
Starling contacts the police departments of the cities where the shops are located, including Pazzi’s department, asking for copies of any surveillance tapes made by cameras installed in the shops. When Pazzi sees one of his men making a copy of such a tape for Starling, he recognizes “Fell” in the tape and decides to find out why the FBI is interested in him. Pazzi accesses the FBI’s database of fugitive criminals and learns that “Fell” is Hannibal Lecter. He also learns that Verger is offering a reward of $3 million to anyone who assists him in capturing Lecter rather than turning him over to the FBI (who offer a $250,000 reward). Hoping to collect the larger bounty, Pazzi makes contact with Verger’s people and agrees to help them kidnap Lecter. Starling, meanwhile, has received the surveillance tape from Florence, recognized Lecter, and learned that Pazzi has been using the FBI’s database to check on Lecter. She calls Pazzi and warns him against trying to capture Lecter himself, but Pazzi ignores her warning.
Pazzi and Verger’s men try to kidnap Lecter after his scheduled evening lecture on the poetry of Dante to a group of scholars at the Palazzo Vecchio, but their plan goes badly awry. Instead, Lecter murders Pazzi by hanging him and cutting out his intestines. He then escapes, deciding to return to the United States to renew his acquaintance with Starling.
Frustrated by the failed attempt to kidnap Lecter, Verger tries to draw him out of hiding once again by getting Starling into more trouble. He bribes Krendler to accuse her of withholding a note she received from Lecter. The ploy works, and Starling is suspended from duty. Verger’s men keep her under surveillance in the hope that Lecter will contact her. Lecter, meanwhile, has been watching her and also watching Krendler. Lecter then buys china and crystal for an elaborate meal—and also steals surgical equipment from a hospital. He takes everything to a secluded lakefront house that he has learned belongs to Krendler.
Lecter then contacts Starling, luring her to Washington’s Union Station for a meeting. Verger’s men follow her there. As Starling looks for Lecter among the crowd of travelers and shoppers at the station, she and Lecter converse by cell phone. He expresses his admiration for her and sympathy for the shabby treatment she has received from the FBI, at one point suggesting that he might force the people who have disrespected her to “scream apologies.”
Having spotted Lecter, Verger’s men capture him in the station’s parking lot despite Starling’s efforts to stop them. Starling makes a fruitless attempt to expose Verger’s scheme to the FBI. Meanwhile, Verger’s men transport Lecter to the Verger estate. Verger plans to watch Lecter being eaten alive by a herd of vicious wild pigs that Verger, an expert at swine breeding from his days in the family meatpacking business, has prepared especially for the purpose.
When the FBI refuses to act on her report that Verger has kidnapped Lecter, Starling goes alone to Verger’s estate. She intervenes as Verger’s henchmen are about to unleash the pigs on Lecter, shooting the men and freeing him—but she is shot and wounded in the process. Lecter then rescues her from the animals. When a furious Verger orders his physician Cordell to shoot Lecter, Lecter persuades Cordell (who has always hated his master) to throw Verger into the pen with the pigs instead, and Verger dies in the very manner in which he had hoped to kill Lecter, Lecter having assured Cordell he will take the blame for the deed.
Lecter takes Starling to Krendler’s lakefront house and treats her bullet wound. She awakens in an upstairs bedroom, dressed for a formal occasion. On her way downstairs, she finds a phone and calls the police. Instead of taking their advice and leaving the house to wait for their arrival, she tries to find Lecter downstairs. She finds him in the dining room where he has set the table as if for an elegant dinner party, watched by the seated Krendler, who has been drugged. As Starling looks on, horrified, Lecter removes the top of Krendler’s skull, cuts out part of his brain, sautees it in a pan by the table, and feeds it to the dazed Krendler.
When Lecter wheels Krendler back to the kitchen to clear up after the “meal”, Starling attacks him with a silver candlestick but is quickly overpowered. Lecter traps her in the kitchen by trapping her hair in the fridge. He asks her “Tell me Clarice, would you ever say to me, ‘Stop…if you loved me, you’d stop’?” To which Starling replies “Not in a thousand years.” Lecter replies with, “That’s my girl,” then kisses Starling. Just as he is about to leave, thinking he’d won, he hears a click and sees that Starling has handcuffed his wrist to hers. When she refuses to provide the key, Lecter pins her wrist to a table and brandishes a meat cleaver. He raises it and says, “This is really going to hurt.”
Next we see Starling outside the house, looking for Lecter, who escaped just before the police cars arrived. Both her hands are intact.
The last scene is of Lecter on an airplane. One of his arms is in a sling. His hand is not visible. He is preparing to eat the boxed meal he has brought with him, and the small boy sitting next to him asks about the food. Lecter opens a container to reveal several kinds of food among whose is what appears to be part of Krendler’s brain, cooked and sliced. The boy asks to try some of the food, and Lecter allows him to, after saying that his mother always told him to try new things.
