When the FBI takes on a case of disappearing college girls, Jack Crawford recruits Will Graham, a gifted criminal profiler with a unique view into the psyche of serial killers, to consult. Jack also seeks the help of Dr. Hannibal Lecter, a brilliant psychiatrist, who, unbeknownst to him, is not only one of the most successful serial killers of all time, but also a cannibal. After a copycat strikes, Will and Hannibal join forces to track down the culprit.
Will Graham is at the house of Thomas and Theresa Marlow, a recently murdered couple. Using his extreme focus and imagination to put himself in the mind of the killer, Will is able to determine the motivation behind the murder, and the methods used to to keep the authorities at bay. Some time later, at the FBI Academy in Quantico, Will lectures his students on the same crime, which remained unsolved.
At the end of the lecture, Will is approached by Special Agent Jack Crawford, the head of the Behavioral Science Unit. Crawford tells Will of a series of eight abductions that have been taking place over the past eight months in Minnesota, with the latest one occurring minutes before Crawford introduced himself to Will. Asking to borrow Will's imagination, Crawford recruits Will to the case as a special consultant. Will believes that the murderer has only one "golden ticket," while the other abductees are merely "candy bars" used to mask the murderer's obsession.
At the victim's house, her parents recall to Will and Crawford that she was supposed to take a train home and feed their cat. Will proposes that since the cat was behaving as usual, Emily did feed it, and was abducted from the family house. Declaring the house as a crime scene, Will enters Elise's room, and discovers her corpse lying in her bed. Realizing the killer brought her body back, Will uses his imagination to conclude that the killer bore down to Elise's ribs (same as a deer when attacking its prey), and strangled her to death.
His imaginative reenactment is disrupted by Beverly Katz, a forensics specialist from Crawford's BAU. She shares with Will that two of the other victims had antler velvet in their wounds, leading Will to believe that this was done by the killer to heal the girls and undo his doings as much as possible. The killer could not do to Elise what he did to the previous victims, which was why he brought her back home.
On his way back home, Will comes across a stray dog, and takes it home with him. Naming it Winston, he introduced him to his other eight dogs. That night, Will has a nightmare in which Elise's corpose is sleeping beside him. He wakes up, drenched in sweat. That next day, Will tells Crawford that this case, and this specific killer, has tested everything he knows about profiling.
One of Will's colleagues, Dr. Alana Bloom, tells Crawford that Will suffers from a large amount of fear while working, and warns him to keep Will away from that environment. In the BAU autopsy room, Katz, along with fellow investigators Jimmy Price and Brian Zeller discovers metal traces from the crime scene. Will concludes that the victim was mounted on hooks by the killer. It is also discovered that the victim's liver was removed, then put back. Will realizes that the killer is a cannibal, and theorizes there was something wrong with the meat. It is soon learned that the victim had liver cancer.
Crawford approaches Bloom's mentor, Dr. Hannibal Lecter, an expert psychologist, whom he hopes to help Will cope with the stress caused by his line of work. At the FBI Academy, Will and Hannibal meet for the first time. Hannibal notices that Will prefers to avoid eye contact, and his ongoing analysis of Will's neurosis proves to be the wrong approach. Will leaves the meeting, but Hannibal still believes he can help Will find the killer.
In a field in Hibbing, Minnesota,, a female victim is found naked, impaled on a deer's antlers. Will believes that the killer, dubbed the "Minnesota Shrike," wanted the police to find her, and is very well mocking them. The lungs of the victim were removed by the cannibalistic killer, and Will believes that he is a copycat. By putting the facts together, Will concludes that the original killer has a daughter of the same age and physical attributes as the victims, whom he is afraid to lose. Meanwhile, in his kitchen, Hannibal cuts up a pair of human lungs and cooks them. Later that night, Will dreams of a deer.
Hannibal surprises Will at his hotel without Crawford, though with breakfast for the two of them. Throughout breakfast, the two engage in a conversation about the copycat killer, who according to Will, tried to show him the negatives of the killing so Will could see the positives of the real Shrike's murders. Hannibal subtly psychoanalyzes Will, and a friendship seems to be building between the two.
After breakfast, Will and Hannibal visit a construction site in relation to the metals found on one of the bodies. Going through the files, Will finds something odd in the file of a pipe threader, Garrett Jacob Hobbs. Besides his recurring absences, Hobbs listed no address in his letter of resignation from his job. Hannibal purposefully drops a box containing the files, and while Will and a secretary gather up the documents, Hannibal sneaks back into the office, dials Hobb's house, and warns him that the FBI knows about his crimes.
Will and Hannibal drive to Hobbs' house, just in time to watch Hobbs open the door and shoves his wife outside, with her throat slit. As Hannibal remains in the distance, Will breaks into the house and shoots at Hobbs, who slits his daughter's throat. Will shoots Hobbs six more times, killing him. Hannibal then aids Will to stabilize Abigail's bleeding. While Hannibal accompanies Abigail in the ambulance, Will arrives at the hospital later during the night. In her room, Will finds Hannibal and Abigail sleeping, with his hand holding hers.
- Will experiences a series of dreams relating to Elise Nichols' murder. (Dreams)
- Will uses his imagination and empathy skills to visualize the murders of Thomas and Theresa Marlow, and Elise Nichols. (Imagination)
- Will dreams of a victim's body being pierced by antlers of a stag, as well as a dream about a stag in a field; a body in a field is found mounted on the antlers of a stag; Katz mentions finding antler velvet in the wounds of the victims; Hannibal's office is decorated by statues and symbols of a stag. (Black Stag)
- The Incredible Hulk. Will's quote "Don't psychoanalyze me. You won't like me when I'm psychoanalyzed" echoes the Incredible Hulk's famous line "Don't make me angry. You wouldn't like me when I'm angry."
- Charlie and the Chocolate Factory: Will constantly refers to Hobbs' obsession with one "golden ticket," while the other victims are just "chocolate bars."