FBI Special Investigator Will Graham (Hugh Dancy), who is haunted by his ability to empathize with serial killers and mentally re-create their crimes with vivid detail, is drawn into the investigation of a series of missing college girls by Special Agent Jack Crawford (Laurence Fishburne), who has special interest in Graham's ability. Crawford and Graham interview the parents of the latest girl to go missing, only to discover that her body has been returned to her bedroom. Graham suspects it is an apologetic gesture from the killer. Crawford, by recommendation of Dr. Alana Bloom (Caroline Dhavernas), enlists the help of noted psychiatrist Dr. Hannibal Lecter (Mads Mikkelsen), who takes a keen interest in the case and particularly in Graham, in whom he senses a like mind. Another girl, Cassie Boyle, is found, this one mounted on top of a deer's head in an open field with her lungs removed. Graham is convinced it is the work of someone else, a negative designed to show him the positives of the other crimes. Dr. Lecter is shown preparing himself a meal with human lungs. FBI crime scene investigator Beverly Katz (Hettienne Park) finds a shred of metal from a pipe threader on the clothes of the returned girl, which leads Graham and Dr. Lecter to a construction site that employs Garrett Jacob Hobbs, who fits Graham's profile. Dr. Lecter secretly makes a phone call to Hobbs, warning him that "they know". Lecter and Graham arrive at Hobbs's house just as Hobbs kills his wife. Graham shoots Hobbs dead, but not before Hobbs partially cuts his daughter's throat. Later, Graham and Lecter sit with the unconscious girl in her hospital room.
Will Graham helps to find a murderer who uses his victims as fertilizer to grow mushrooms. Tabloid blogger Fredricka "Freddie" Lounds (Lara Jean Chorostecki) snoops around the crime scene and Dr. Lecter's office to write a story about Graham, which the killer uses to stay a step ahead of the investigation. Meanwhile, Graham and Dr. Lecter discuss their mutual feeling of responsibility for Abigail Hobbs (Kacey Rohl), which leads Graham to begin opening up to the doctor. The killer is revealed to be a pharmacist who preys on diabetics and is obsessed with the similarities between the structures of fungi and the human mind: Graham intercepts and shoots him in the arm as he attempts to kidnap the unconscious Abigail Hobbs. During another session with Lecter, Graham reluctantly admits that he found killing Garrett Jacob Hobbs "just"; Lecter likens it to a feeling of being God.
Abigail Hobbs awakens from her coma. Graham suspects that Garrett Jacob Hobbs, dubbed the Minnesota Shrike, killed eight girls, but not the one impaled on the deer's head; that, he maintains, was a victim of a copycat, who called Hobbs to warn him. Crawford harbors suspicions that Abigail was somehow complicit in her father's killing spree, despite objections from Dr. Bloom, Lecter and Graham. Lounds meets the brother of the impaled girl and reveals to him that Abigail Hobbs is out of the hospital. Lecter and Graham take Abigail to her home, where she and her neighbor Marissa are confronted by the brother of the impaled girl, Nicholas Boyle. The following day, Abigail is taken to the cabin where Marissa is found impaled on a deer's head. In her house, Abigail finds the hair of one of the murdered girls inside a pillow and inadvertently kills Boyle in a way that, according to Lecter, cannot be seen as self-defense. Lecter helps her cover-up the murder, after which Abigail realizes it was Lecter who made the call to her father. Lecter suggests that Abigail keep his secret in exchange for his hiding her murder.
Two families are found murdered, with both mothers killed last. The only link between the families is that they both have sons who have been on the missing persons list for approximately a year. Graham concludes these "lost boys" are killing their old families to bond more closely to their new family. Graham continues his sessions with Dr. Lecter and confides that even if he finds the boys, he will never be able to give them back what they gave away: their families. He also admits to having paternal feelings toward Abigail Hobbs, which make him uncomfortable. Lecter's own interest in Abigail leads him to check her out of the hospital, against Dr. Bloom's wishes, and take her into his care. He gives her some tea made from psilocybin mushrooms to help with her traumatic dreams. Bloom helps Graham realize that the boys are under the influence of a powerful but unnamed mother figure (Molly Shannon) and uses footage from a convenience store security camera to track them to North Carolina in time to stop another young boy from murdering his family.
A murdered couple is found in a motel room, posed in praying positions with the flesh of their backs opened and strung to the ceiling to give them the appearance of wings. Using a sample of the killer's vomit found on the nightstand, the BAU team discover several medications often used together to treat cancer, specifically brain tumors. Graham surmises the killer is transforming his victims into guardian angels to watch over him because he is afraid of dying in his sleep. Meanwhile, Crawford's wife Phyllis "Bella" (Gina Torres) becomes Dr. Lecter's new patient. She is reluctant to tell her husband that she has terminal lung cancer because he already has too much to worry about. Graham starts to suffer from episodes of sleepwalking and continues to dream about the feathered stag that has been haunting him since the Hobbs case. He confides to Dr. Lecter that the pressure of looking into killer's minds is starting to break his psyche and Lecter attempts to use this to create a wedge between Graham and Crawford. The angel maker is tracked to an old farm, but is discovered to have committed suicide and transformed himself into an angel. During the investigation, Crawford realizes the reason for his wife's distant behavior and promises to help her through her illness any way he can.
A nurse at the Baltimore State Hospital for the Criminally Insane is brutally murdered by a patient, Dr. Abel Gideon (Eddie Izzard), in a manner reminiscent of the Chesapeake Ripper, who hasn't committed a murder in two years, the same number of years Gideon has been incarcerated. While Graham tries to discover whether Gideon truly is the Ripper, Crawford receives a phone call, apparently from the real Ripper, who plays the recorded voice of Miriam Lass (Anna Chlumsky), a trainee Crawford had consulting on the Chesapeake Ripper case two years previously when she suddenly disappeared. Bloom and Crawford make a deal with Lounds to write a story about Gideon, hoping to provoke the real Ripper to make himself visible. During a dinner with Bloom and Lecter, Dr. Frederick Chilton (Raúl Esparza), the administrator of the hospital, tells them he had suspected Gideon of being the Ripper; Lecter surmises that Chilton unintentionally planted the thought in Gideon's mind during a session, implying that, while Gideon is not the Ripper, he believes himself to be. Later, Crawford receives another phone call, which they trace to an old observatory, where they find Miriam's cell phone clutched in the hand of a severed arm. A final flashback reveals Miriam's fate: she visits Dr. Lecter to ask about an old patient, Jeremy Olmstead, whom he had come into contact with when working as an ER attendant, who has turned up as the latest Ripper victim. While Lecter excuses himself, Miriam finds one of his sketches of the Wound Man, which precisely matches the manner in which Olmstead was murdered. Lecter sneaks up on her from behind and chokes her unconscious, revealing himself as the real Chesapeake Ripper.
The BAU is called in when a man is found in a hotel room bathtub with his kidney removed and Graham must determine whether this is the act of an organ harvester or if the Chesapeake Ripper has claimed his first victim in two years. Meanwhile, Crawford continues to be haunted by the discovery of Miriam Lass's arm. Dr. Bloom suspects that Crawford has become obsessed with catching the Ripper, and is putting Graham in danger by making him chase the Ripper. Lecter murders a medical examiner who once treated him rudely and removes his heart. When his body is found displayed on a bus, Graham becomes convinced that the latest victim was the work of the real Ripper, while the first was not. Lecter takes another four victims and harvests their organs for use in a dinner party. Through hotel security footage, the BAU team discovers that the organ harvester is a part-time paramedic, Devon Silvestri, who aspires to be a doctor. They track his ambulance in time to save the life of his latest victim, but his arrest solidifies Graham's opinion that there is only one Chesapeake Ripper, who was responsible for all of the murders except the first.
Lecter's patient Franklyn Froideveaux (Dan Fogler) worries that his friend Tobias Budge (Demore Barnes) may be a psychopath, but Franklyn's growing obsession with Lecter is what concerns the latter more. Graham investigates the murder of a Baltimore musician who had his throat opened and a cello neck inserted through his mouth. Graham, with Lecter's guidance, interprets this as one killer serenading another. Graham's mental stability deteriorates further when he begins having auditory hallucinations of animals in pain and when his romantic feelings for Alana Bloom are rejected. At first she responds well to Graham kissing her, but then says it would be a bad idea for them to become involved. When Franklyn confesses to Lecter that Tobias had told him he wanted to cut open someone's throat and "play them like a violin", Lecter confronts Tobias, who reveals that not only is he the murderer, but he knows that Lecter is one as well and feels they could be friends. Lecter passes on some of this information to Graham, once again putting an unknowing Graham in a dangerous situation when he goes to question him. Tobias kills two police officers who had accompanied Graham and escapes to Lecter's office, where Franklyn is having a session. Lecter kills both Franklyn and Tobias and lies to Crawford about what happened. Lecter confides to his own psychoanalyst, Dr. Bedelia Du Maurier (Gillian Anderson), that he believes he might have found a true friend in Graham.
The totem pole of human bodies ranging from freshly killed to decades old are found on a beach and while Graham is investigating the crime scene, he suddenly finds himself in Lecter's office, three and a half hours away, with no recollection of how he got there. Lecter theorizes that Graham's mind is trying to escape from having to investigate such brutal murders. Lounds convinces Abigail Hobbs to let her write a book about her and her father, which is met with grave concern from Graham and Lecter. The body of Nicholas Boyle (whom Abigail had accidentally killed) re-surfaces and with it re-emerges Crawford's suspicion that Abigail knows more than she is letting on. The freshest totem pole victim is identified as Joel Summers, who was the son of Fletcher Marshall, the oldest body on the pole, before he was adopted. The killings are traced to Lawrence Wells (Lance Henriksen), who was having an affair with Marshall's wife and killed him in a crime of passion. The rest of the killings were for his own satisfaction; knowing he'd be caught, he could "retire" to a life in prison, which would be better than any retirement home he could afford. However, Graham reveals that Summers was not Marshall's biological son, he was Wells', who unknowingly murdered his own son. Graham examines Boyle's body and deduces that he was killed by Abigail. He confronts Lecter, who reveals that he helped Abigail hide the body in order to protect her future. Graham reluctantly agrees to keep her secret so that she won't inherit her father's brutal legacy. Abigail herself reveals an even greater secret to Lecter: that she actually did, as Crawford suspected, know who her father really was and helped him to procure his victims by befriending the young girls.
Beth LeBeau is found murdered, having drowned in her own blood as a result of her face being cut into a glasgow smile. Graham's mental state continues to sharply decline; he loses hours at a time and when a vivid hallucination causes him to contaminate the crime scene, Lecter refers him to a neurologist, an old residency colleague, Dr. Sutcliffe (John Benjamin Hickey). An MRI reveals that Graham is suffering an advanced form of encephalitis, but Lecter pressures Sutcliffe into telling Graham that he found no neurological problems so that Lecter can continue to analyze him. Graham returns to LeBeau's house, where he is attacked by her killer, who manages to escape. She is identified as Georgia Madchen (Ellen Muth), a young woman who suffers from numerous medical conditions, including Cotard's syndrome, a delusional disorder that has her convinced she is actually dead and takes away her ability to identify people's faces. She mutilated LeBeau's (her best friend) face because she was deluded into thinking LeBeau was an untrustworthy stranger. She becomes interested in Graham after their encounter and even follows him to Dr. Sutcliffe's office. Graham reaches out to her and manages to convince her that she is alive and not alone, and Georgia is brought in for medical treatment. Lecter murders Dr. Sutcliffe but frames the kill to appear as though Georgia had murdered him while following Graham.
Dr. Abel Gideon escapes from custody and begins targeting the psychiatrists who attempted to treat him, displaying their bodies with a Colombian necktie. While Alana Bloom is put under protective custody, Gideon kidnaps Dr. Frederick Chilton and lures Freddie Lounds into a trap, forcing her to write an article about him. Meanwhile, Graham's undiagnosed encephalitis drives his temperature up, causing severe hallucinations. Another psychiatrist is found similarly mutilated, only with his right arm amputated and Graham speculates that this is actually a message from the real Chesapeake Ripper telling them where to find Gideon. At the abandoned observatory where Miriam Lass' severed arm was found, Gideon begins surgically removing Chilton's organs with the intention of leaving a "gift basket" for the Ripper, whom Gideon is trying to lure out. While Crawford and a SWAT team hit the observatory, Graham's hallucination of the stag returns and he follows it, fortuitously intercepting Gideon, who had anticipated the SWAT team's arrival. In his delusional state, Graham takes Gideon to Lecter, who convinces Graham that he has hallucinated the encounter. When Graham has a seizure, Lecter uses the opportunity to set Gideon on Alana. Lecter manipulates Graham into pursuing him and Graham shoots at Gideon outside Alana's house before collapsing. Graham is hospitalized.
Following an offhand comment by Graham, Hannibal leaves a comb in the chamber of Georgia Madchen, who accidentally sparks a fire inside her hyperbaric chamber and is burned to death. Angered, Graham deduces that several recent murders were all the work of a copycat patterning after recent serial murders, and that Georgia was killed because she may have remembered the face of whoever had killed Dr. Sutcliffe. Crawford, bothered by Graham's behavior and by Lecter's apparent concealment of Graham's hallucinations, discovers the pattern that shows Abigail was present during Garrett's victim selection processes. Crawford confronts Lecter's therapist, Dr. Du Maurier, and she later tells Lecter that she didn't reveal the details about being attacked by a patient. After releasing himself from the hospital, Graham takes Abigail back to Minnesota, to the hunting lodge. During a hallucination he deduces, correctly, that Abigail was an active participant in her father's murders. Fleeing from Graham, Abigail is comforted by Lecter, who admits to having killed more people than her father. When Abigail asks him if he is going to kill her, he simply tells her that he is sorry he couldn't protect her.
Following his strange trip to Minnesota, Graham is taken into custody by Crawford for the probable murder of Abigail Hobbs. They find her severed ear in his kitchen sink and her blood under his fingernails. Alana is left devastated by the arrest and is determined to find the cause of Graham's dementia, despite Crawford's insistence that there is no underlying cause. She has him draw a clock when he tells her that Dr. Lecter had him perform a similar test, and the results solidify her belief that there is a physical explanation for Graham's instability. Katz, Price and Zeller examine Graham's homemade fishing lures and discover that four of them have included elements of human remains, whose DNA matches all four victims of the copycat killer: Cassie Boyle, Marissa Schur, Dr. Sutcliffe and Georgia Madchen. Graham escapes from custody while being transferred and goes to Lecter for help, only to have Lecter demonstrate that it is feasible for him to have murdered all four people. Graham convinces Lecter to take him back to the Hobbs house in Minnesota, where he finally comes to realize that it was Lecter who called to warn Garrett Jacob Hobbs about his impending arrest and that Lecter has been manipulating him ever since to see how someone with Graham's unique ability would operate. Crawford arrives and stops Graham from killing Lecter by shooting him in the shoulder. Graham is hospitalized, where his encephalitis is finally discovered and he is placed in a protective coma while undergoing treatment. Lecter brings dinner to Du Maurier, where she reveals that she may know much more about him than even he suspected. Next, Lecter pays one last visit to Graham in his new home: the Baltimore State Hospital for the Criminally Insane.