Ten years after his escape from custody, the infamous Dr. Hannibal Lecter resides in Florence, Italy, basking in the arts and savoring the freedom from his criminal past. Despite his attempts to elude his former life, Lecter remains the subject of an intense manhunt led by the FBI. Special Agent Clarice Starling, haunted by her earlier interactions with Lecter and facing scrutiny within the FBI, is deeply affected by her past connection to the erudite but psychopathic killer and is drawn back into the pursuit. Meanwhile, in Italy, Lecter's presence has drawn the attention of a local police detective, who unravels clues about the fugitive's identity and attempts to capture him for the reward.

Simultaneously, a disfigured, vengeful billionaire named Mason Verger, one of Lecter's surviving victims, obsessively seeks his own form of justice. Using his vast resources, Verger orchestrates a wicked plan to draw Lecter out. He leverages his influence on law enforcement and employs a network of criminals to track down the exiled predator. Tensions escalate as Lecter navigates through the web of intrigue, with Starling's involvement becoming more personal and her resolve tested to its limits as she delves deeper into the twisted world of her adversary. The stakes rise as each party races to capture Lecter, leading to a deadly game of cat and mouse that intertwines the fates of all involved.