After a particularly grueling case hunting a serial killer known as the Minnesota Shrike, Will Graham threatens to walk away. Jack Crawford, the head of the FBI's Behavioral Science Unit, desperately needs Will on his team to break the tough cases, so he enlists Dr. Hannibal Lecter, to ensure Will's mental well-being. Unbeknownst to Will, Hannibal also has a particular insight into these horrible crimes and the psychopaths who commit them. As Will hunts down brutal killers, he is unknowingly sitting across from the most gifted killer of them all.

After being sworn in by Jack Crawford, the head of the FBI Behavioral Science Unit, to help capture a serial killer who is on the rampage, Will finds himself increasingly struggling to control his thought processes that inform his uncanny ability to empathise with serial killers. When damning evidence shows up at the FBI that implicates Will in a string of grisly murders he is immediately placed under the care of the Baltimore State Hospital for the Criminally Insane. As Will tries to assure Jack of his innocence he also attempts to convince him of the identity of the real killer.

After the shocking events of the Season 2 finale, Hannibal is on the run in Europe - accompanied by his psychiatrist Bedelia Du Maurier - sporting a new identity, but servicing the same insatiable appetite. As the lives of Will, Jack and Alana converge toward Hannibal again, each with their own motivations to catch him once and for all, their deadly dance turns in startling and unexpected ways.