Having eluded capture from the FBI, Hannibal settles down in Italy with Bedelia Du Maurier under assumed identities. However, Bedelia is ever uneasy about her company with Hannibal just as a kink presents itself in his new alias.
8 months after being left to bleed to death, Will is in Italy in search of Hannibal. There he finds himself at the Norman Chapel where a heart-shaped body has been left. Still feeling Hannibal's pull, Will is approached by Chief Investigator Rinaldo Pazzi who believes Lecter is the killer he sought 20 years ago: the Monster of Florence.
In his pursuit for Hannibal, Will journeys to Lithuania. Coming to his childhood home, Will encounters a woman who has long been guard to a dark part of Lecter's past.
As the dust settles on the aftermath of their near-fatal attack, Will, Alanna, and Jack try to move on from their wounds. As Jack does his best to cope with his worsening wife, a scarred and bitter Chilton approaches fellow survivors Will, Alanna, and Mason Verger regarding retribution against Hannibal.
The hunt for Hannibal begins. Will travels via train with Chiyoh to Florence, as Alanna and Mason use Hannibal's fine tastes to track his whereabouts. Pazzi tries to get in close to find out if Hannibal is the man he's looking for, but his greed may get the better of him.
With Bedelia securing her alibi, Hannibal prepares to leave Florence just as Jack and Will begin to track him down. With Pazzi murdered, Mason and his cohorts consider a different course of action. However, Chiyoh has arrived in Florence with her own agenda.
With Hannibal in his custody, Mason prepares to savour his revenge. However, Alanna is uneased when she learns that Will is part of his plot. Meanwhile, Margo learns that Mason has found a surrogate for the eggs he removed from her.
It's been 3 years since Hannibal turned himself in to the FBI and Will has long left behind both. However, he is approached by Jack to track down a killer nicknamed the Tooth Fairy who murders whole families.
Will visits Hannibal to aid in his investigation of the Tooth Fairy killer, which concerns Alana. Meanwhile, the killer, Francis Dolarhyde meets and takes an interest in a blind co-worker.
Dolarhyde's relationship with Reba grows, causing conflict with his becoming of the Great Red Dragon. Will visits Bedelia for further insight.
With the Great Red Dragon compelling Dolarhyde to take Reba, Hannibal offers him Will's family. Alana and Jack discover Hannibal's contact with Dolarhyde and make him a deal.
As Will begins to to slip into Dolarhyde's mind, Dolarhyde is himself further consumed by the Great Red Dragon. Will, Jack, and Alan plan a dangerous trap to lure the Dragon out. It's not long before they have to face the unfortunate, but inevitable consequences.
Aware that Dolarhyde wants to meet Hannibal, Will devices a plan to use him as bait. To everyone's horror, it involves staging Hannibal's escape.