While stalking Dr. Roman Fell (Jeremy Crutchley) to a party held in Paris, Hannibal Lecter becomes acquainted with Anthony Dimmond (Tom Wisdom). They discuss poetry and Dr. Fell, for whom Dimmond served as a TA. Lecter follows Dr. Fell to his house, killing him and (presumably) his wife. Through flashback, Abel Gideon is seen eating his cooked body with Lecter, where he comments that Lecter is truly a personification of the Devil. Lecter and Du Maurier are shown as having traveled to Florence, Italy, where they are assuming the identities of Fell and his wife. Through flashback, Du Maurier enters her house some hours after being interviewed by Crawford and discovers Lecter in her shower. She pulls a gun on him, and they discuss what Lecter has done, their relationship, and Graham. In present day, Dimmond arrives in Florence and is invited to Lecter's house for dinner. Through flashback, it is shown how Lecter prepared Gideon's severed arm for consumption - he had fed Gideon oysters, sweet wine, and acorns to enhance Gideon's flavor for the snails fattening themselves on it. Gideon comments that it won't be long until Lecter is himself cannibalized. Over dinner, Du Maurier is revealed to being given the same treatment, as Dimmond reveals that the Romans are the originators of that practice. Through flashback, Du Maurier murders Lecter's former patient Neal Frank (Zachary Quinto), who was transferred to her, causing her to owe a debt to Lecter in return for his help.

Will Graham awakes in the hospital after being near-fatally stabbed by Hannibal Lecter. Will's attending physician tells him he has a visitor. This turns out to be Abigail Hobbs, whom Will last saw as Dr. Lecter slashed her throat. Abigail explains that they are both alive because their wounds were "surgical" and Lecter knew just how to cut them so they'd both live. Abigail is angry at Will for lying to her and trying to capture Lecter, in whom she still believes. Abigail is shown with Will eight months later, when he has traveled to Palermo in pursuit of Lecter. In a cathedral, Will meets Rinaldo Pazzi (Fortunato Cerlino), who has read up on Will's arrest for the Chesapeake Ripper killings. Pazzi has been following Lecter since seeing him as "a young Lithuanian man" and investigating a murder for which another man was convicted, inspired by the Botticelli painting Primavera. Pazzi shows Will a photograph of the origami heart Lecter made of Dimmond (having folded his body up). While talking to Abigail, Will remembers that she died of her injuries before he recovered from his, and that he has been talking to a hallucination. She disappears. Will and Pazzi pursue Lecter through the catacombs under the cathedral, but he eludes them. Before leaving himself, Graham senses Lecter is nearby, and tells him he forgives him.

Will travels to Lecter's childhood home in Lithuania in further search of his nemesis. Lecter and Du Maurier continue to discuss Graham and the fact that Lecter is drawing Graham and "all of them" to him. Jack Crawford arrives in Palermo in search of Will. Pazzi shows Crawford the case photographs of Dimmond's heart, and they have a conversation about Lecter. Will discovers a distraught man in an underground cell (Julian Richings), where he meets Chiyoh (Tao Okamoto), the attendant to Lecter's aunt. She reveals that Lecter's sister, Mischa, was murdered and cannibalized by the prisoner. Graham doesn't believe this. Elsewhere, Du Maurier asks Hannibal about his past and he tells her about Mischa. Du Maurier deduces that Hannibal ate Mischa to "forgive her". Chiyoh asks Graham why he is still searching for Lecter. He responds that he has never known himself better than when he is with Lecter. Graham removes the prisoner from the cell and turns him loose; he attacks Chiyoh but she kills him. Distraught at what she has done, she realizes that Graham set the man free on purpose to see if she was capable of killing, confirming Lecter's curiosity. Chiyoh agrees to help Will find Lecter, saying that with the prisoner dead, she has no reason to remain at the house. Before they leave, Graham fashions the corpse of the prisoner into the form of a dragonfly, and displays it in the underground chamber. Lecter and Du Maurier have another discussion about Graham and come to the conclusion that the only way for Lecter to forgive him is to eat him.

Frederick Chilton meets with Mason Verger (Joe Anderson), where they discuss Lecter after revealing their disfigurements, then goes to meet Graham. Crawford recalls his meeting Graham after the events at Lecter's house, with Graham stating that he informed Lecter of his and Bloom's impending arrival because he considered Lecter a friend, and wanted to run away with him. Chilton goes to Bloom, who has agreed to act as Verger's new therapist. In a flashback where both Crawford and Bella are bedridden (Crawford right after the events of last season's finale), Bella comforts Crawford, but says "at least you can cut out what's killing you." Chilton asks for Crawford's help, telling him that Graham will lead him right to Lecter, but Crawford refuses to get involved, stating that he has let everything go, and that he's focusing on caring for his wife. Bella succumbs to her cancer, and at her funeral, Crawford is upset to notice a card from Lecter offering his condolences. Graham enters the church, where Crawford says he knows what's coming for him, and that he does not have to die. Verger asks his physician Dr. Cordell Doemling (Glenn Fleshler) to make arrangements for Lecter to be eaten alive. During a session with Verger, Bloom agrees to help him lure Lecter to what he is planning. Crawford meets Bloom at Will's house; she says that Graham has already left. Graham is seen leaving on a boat.

Graham and Chiyoh travel by train to Florence, discussing her relationship with Lecter. In Florence, Du Maurier and Lecter discuss Graham and the fact that Lecter is lying in wait to kill him once he arrives. Crawford releases his wife's ashes into the river as well as his wedding ring, and has dinner with Pazzi and his wife (Mía Maestro), who are newly married. Pazzi says that he'll tell his subordinates that he's investigating Lecter when he knows for certain it's him; Crawford tells him he already knows. Bloom reveals to Verger that a blonde woman has been shopping for Lecter. Graham and Chiyoh continue to have conversations. Pazzi goes to meet Lecter, probing for information about the two murdered professors. Pazzi ultimately decides to sell Lecter to Mason Verger, a fact of which Lecter is already aware. Graham awakens to find Chiyoh outside, where she tells him that she knows Lecter is in Florence; doubting their alliance, she throws him from the train, and he is forced to continue his journey on foot. Pazzi has a video contact with Verger, who lays out the terms of his bounty, which includes a fingerprint. Pazzi goes back to Lecter with a gift for his exhibition. Lecter in turn presents an heirloom for Pazzi, an illustration of his ancestor's murder. As Pazzi goes for a knife with Lecter's fingerprint, Lecter overpowers him. Lecter has tied Pazzi to a hand truck, and while preparing to hang him with an orange power cord, he ascertains that Pazzi is working with Verger, and asks if any other authorities know. As Pazzi answers, Lecter is interrupted by a call for him from Bloom, which he answers. Before he hangs Pazzi, he cuts his belly, allowing his bowels to spill as in his ancestor's death. Crawford arrives, looking for Pazzi. A fight ensues, during which Lecter taunts Jack about the death of Bella and is brutally beaten as a result. Jack attempts to push Lecter from the same balcony window, but he arrests his fall by grabbing onto Pazzi's corpse, and having survived the fall, stumbles away.

Will arrives in Florence where he meets Jack and they discuss how to proceed in the search for Lecter. Their first stop is the house where he was staying as Dr. Fell. Dr. Du Maurier has stayed behind after coming to an agreement with Hannibal to support each other's stories. Altering her own responses by shooting heroin, she clings determinedly to her identity as Mrs. Fell, even though Will and Jack both know her as Du Maurier. Back in Baltimore, the Vergers and Alana go over the bounty for Lecter. After it's confirmed that Pazzi has been killed in pursuit of Lecter, Alana suggests that they may need an entire department. Margot leaves to make arrangements. Mason asks Margot what she wants and she reminds him that he took away her ability to have children. He raises the possibility that she could still have a child with him. Afterwards, Margot has a sexual encounter with Alana and asks if Alana knows how to harvest sperm. An inspector from the police headquarters in Florence comes to interrogate Du Maurier and speaks to Jack about Lecter's history in America. Will goes to a gallery where he meets Lecter. The two men have a civil discussion, but when they leave Will takes out a knife to kill Lecter. Before he can do so, Chiyoh shoots him from a nearby roof with a sniper rifle. Lecter takes Will to another hideout and removes the bullet. Jack tracks Will to where Lecter is keeping him and attempts to free him. Lecter ambushes Jack, slitting his Achilles' tendon and tying him to a chair at the dining table. He begins to cut into Will's head with a cranial saw. Will and Lecter are brought to the Verger home.

The Florentine police intercept the meeting between Jack Crawford, Hannibal Lecter and Will Graham. The police capture Lecter and a wounded but alive Graham to give to Mason Verger on accounts of the bounties both set on them. The police attempt to kill Crawford but are shot dead by Chiyoh from a nearby roof top. Crawford informs Chiyoh that Graham and Lecter are being taken to Muskrat Farm, property owned by Mason in Maryland. Chiyoh sets Crawford free as he questions how he will escape Florence without being killed by the police. Meanwhile, Mason and Cordell await the arrival of Lecter and Graham with plans of eating Lecter after transplanting Graham's face onto Mason's. Alana Bloom and Margot Verger begin to arrange ways to receive a child from Mason's viable sperm with the possibility of Alana as a surrogate. Margot reveals to Mason and Alana that Crawford is still alive which worries Mason that the FBI could arrive soon. Hannibal, Will, and Mason eat dinner together discussing how the plans will be carried out. Will bites off part of Cordell's face in protest. Cordell stitches his cheek and converses with Lecter over how Mason will devour him. Mason reveals to Margot that he has already prepared a surrogate of his own for their child that is on the farm. Alana explains her alliance with the Vergers with Will. Margot converses with Lecter about her longing for a child and resentment of Mason. Lecter suggests that, for therapeutic reasons, Margot should kill Mason after she receives the child and he will take the blame. Alana shoots Lecter's guard and sets Hannibal free with a promise that he will rescue and keep Will alive. Mason is put under anesthesia for the facial treatment while Cordell does not use any on Will.

Francis Dolarhyde (Richard Armitage) sits in a cafeteria and begins reading a copy of Time covering The Great Red Dragon Paintings. He is so enamored with the image that he begins to mold himself into a version of the paintings, having The Great Red Dragon and the Woman Clothed in Sun tattooed on his back and purchasing a set of custom-made jagged dentures. Three years after the events of the previous episode, Lecter has been institutionalized and Bloom is now the administrator at the hospital, due to Chilton resigning to become a best-selling author of true crime volumes. Dolarhyde practices speaking with his cleft upper lip and is then seen standing naked outside a home, covered in blood and staring up at the full moon. Chilton has dinner with Lecter in his cell, where he reveals his next book is about Dolarhyde, who has been given the nickname The Tooth Fairy. He has a conversation with Bloom, where she reveals that Lecter has written an article for the American Journal of Psychiatry refuting much of what Chilton has written about him. He suggests that Dolarhyde will inspire Lecter to "keep himself interesting". Dolarhyde is seen watching film when the projector blows out; he has a hallucination. He compiles news clippings in a large book, detailing not just his own crimes but articles on Lecter. Crawford goes to visit Graham, who is now living with his new wife Molly (Nina Arianda) and her eleven year-old son. Crawford has come to get Will's assistance on the Dolarhyde killings, but he is highly resistant after his previous experiences.

Lecter agrees to discuss the Dolarhyde murders with Graham, saying that he is family. Through flashback, Lecter takes Abigail Hobbs' blood, and says that he needs to collect a flesh sample. They spray her blood throughout the room, creating a staged crime scene. While waiting for Lecter to read through the case file, Graham has a conversation with Bloom, where she reveals that she and Margot are still together; she carried their child, a boy. Graham tells her not to worry about him. Bloom tells him that she is not just worried about him, but that last time it did not end with him. Graham and Lecter have their discussion. Bloom visits Lecter afterward, stating that he does not have Graham's best interest at heart, and warning him that the improvements to his cell are conditional; the conditions are non-negotiable. Through flashback, Lecter has a therapy session with Abigail, where he has placed her father's body in a chair, and states that he showed her love by cutting her throat. He tells her that she is denying his love because of what it might say about her, and asks her to show him the same courtesy; she slits his throat. Graham watches video of a family that was murdered; Dolarhyde watches film and writhes in pain; he has hallucinated growing a tail. Price, Zeller, and Graham discuss the murders further with Crawford. Graham goes to a crime scene, where he meets Lounds, where he berates her for taking photos of him in the hospital, and writing that he and Lecter were co-conspirators. Dolarhyde is seen reading Lounds' report. He goes to the film developing lab where he meets Reba McClane (Rutina Wesley), a blind woman.

Dolarhyde practices speaking before going to an electrical outlet facility and enabling contact from Lecter's former office. He calls Lecter under the guise of his lawyer and they have a quick exchange. He hallucinates a session between himself and Lecter; at the end of the session, he transforms into a dragon. Graham attends an academic tutorial by Du Maurier, and the two have a conversation afterward regarding their experiences with Lecter. Dolarhyde takes McClane to a zoo to experience the sensation of touching and feeling a tiger. They spend the night together at his home. When Dolarhyde awakens, he feels McClane, and is then overtaken by another hallucination. When he awakens again, he notices McClane is not there. In a panic, he runs to the room with the copy of the painting, and senses a communication to make McClane his next victim. He takes her home, refusing the temptation. Lecter takes a call from his cell to his lawyer, but then hacks the phone and asks the operator to call a different number – Chilton's office. Posing as a publishing executive, he asks for an address and number – Graham's. Graham and Du Maurier have a session, where they discuss her relationship with Lecter. Du Maurier recalls her session with Neal Frank, where he stipulates that there was something wrong with Lecter, judging by the way in which he ended their relationship. Frank states that under Lecter's so-called care, his paranoia worsened, and has refused to take Lecter's prescribed medication. He continues to berate Lecter's methods, saying that he nearly choked on his tongue after a disguised photo-therapy experiment. The scene cuts to Graham's session, where Du Maurier asks him if he thinks he can save Dolarhyde from himself after failing to do so with Lecter. Cutting back to another of Frank's sessions, he berates Du Maurier for not taking action against his accusations of Lecter. He asks if she believes him. Du Maurier states that she believes Frank is suffering from a lack of insight, and that she is trying to help him regain that insight, and would prescribe the same medication that he refused.

Graham, Bloom, and Crawford discuss the events at the museum. Dolarhyde has another session with Lecter over the phone where he suggests going after Graham's family to appease the dragon, sparing McClane. Dolarhyde seemingly transforms into the dragon back at home. He spends another night with McClane, where he has gathered film of his victims and selected victims, and watches a selection with an unknowing McClane – Graham's family. Molly and Walter go to the veterinarian after their dogs have been poisoned. They promise not to tell Graham, and as they leave, a notice from the FBI asking to immediately report any pet mutilations is shown on the bulletin. Graham visits Lecter where he deduces that Dolarhyde has contacted him. He asks Lecter to tell him who Dolarhyde is, saying that they can save the next family; Lecter states that he does not know who Dolarhyde is, and asks Graham if when he closes his eyes, is it his family he sees as the next target. Dolarhyde travels to the Graham's residence to murder Molly and Walter; they narrowly escape, but Molly is hospitalized. Graham has a conversation with his stepson in the waiting room before going to see Molly. Bloom arrives with Crawford at Lecter's cell, where they tell him that they know he has been talking to Dolarhyde under the guise of receiving calls from his lawyer. They ask him to cooperate in trying to identify Dolarhyde the next time he calls. Back at home, Dolarhyde has a hallucinogenic fight between himself and the Dragon.

Graham has another session with Du Maurier where he states that he has been having visions of himself murdering his family in the manner of Dolarhyde. Du Maurier says that Lecter spent three years waiting for Graham to start a family so he could take them from him. Graham asks Du Maurier what Lecter is going to take from her; she says that Lecter is in no position to kill and eat her, and that he has paid dearly and that it excites him. Graham asks if Lecter is in love with him. Du Maurier states that he is and asks Graham if he feels the same way. Crawford speaks with Lecter. Dolarhyde kneels to the painting in his house, and begins to tear his own flesh. Graham, Bloom, and Crawford devise a plan to bring Dolarhyde out by using Chilton and Lounds. Chilton visits Lecter and berates him for refuting his work. The setup for Dolarhyde takes place, where Chilton and Graham spew insulting remarks about him, as well as taking a photograph together for an article that Lounds will publish. Graham and Crawford have a conversation outlining the plan to catch Dolarhyde when he goes after Graham, instead, Dolarhyde captures Chilton and takes him to his house. He glues him to a wooden wheelchair and verbally torments him. McClane comes by briefly, believing Dolarhyde to be ill, having brought soup. They have a quick conversation before she leaves. With her gone, Dolarhyde torments Chilton further, showing him slides of The Great Red Dragon Paintings as well as "transformed" victims before showing the photograph taken to lure him. Chilton states that he does not want to die, and Dolarhyde asks him if he will now tell the truth about him. He tapes Chilton refuting his accusations, and says that he will let him go, but that there is a better way for him to understand and remember what he is; Dolarhyde bites Chilton's lips off with his dentures and mails them to Hannibal. They are delivered to Lecter by Bloom, and Hannibal eats one of the lips.

Dolarhyde, not wanting the Dragon to harm McClane, stages his suicide while allowing her to escape his mansion under the belief that he is dead. He ambushes Graham in his motel room and demands that he lead him to Lecter. Crawford and the rest of the team quickly discern that the body found in Dolarhyde's mansion was not his. While brainstorming ideas for how to catch Dolarhyde, Graham suggests using Lecter as bait by staging his escape from the hospital. Lecter agrees to this plan, but only after Graham personally requests his participation. Crawford and Bloom plot to kill both Lecter and Dolarhyde once the bait is accepted. In a session with Du Maurier, Graham reveals his intentions of Lecter not being recaptured, leaving unstated whether that means his death or freedom. As the plan is implemented, Lecter's convoy is unexpectedly ambushed by Dolarhyde, who kills all of the FBI and police personnel while sparing Graham and Lecter and allowing them to flee. They travel to the cliff-side house where Lecter had previously kept Abigail Hobbs and Miriam Lass as his captives. There, Dolarhyde, having pursued them, attacks again, shooting Lecter in the stomach and stabbing Graham in the face, intending to kill both on film. Graham and Lecter, working together, overpower Dolarhyde and kill him. Both soaked in blood, Graham embraces Lecter, and then pulls them both over the cliff to ambiguous fates. In a post-credits scene, Du Maurier sits at a table set for three, her own left leg severed, cooked and prepared as an entrée much like Gideon's.