A graphic double murder has taken place in a residential neighborhood. Will Graham, a brilliant but socially awkward savant, is examining the crime scene. Putting himself in the mind of the criminal, Will uses extreme focus to hone in on the details of the murder. Every bullet was shot with expert precision. The killer tapped the phones in the house a week prior in order to record a conversation between one of the victims and her security company. When the murder was committed, the culprit played her voice back to keep the authorities at bay. Whoever did this was a pro.
At the F.B.I. Academy in Quantico, Will Graham lectures trainees on the unsolved crime. Afterwards, he is approached for help by the lead of the Behavioral Science Unit, Special Agent Jack Crawford. Over the past eight months, eight girls have been abducted from Minnesota campuses. The most recent abduction occurred only moments before Jack introduced himself. Will thinks one of the eight is a "golden ticket" and the rest are just "candy bars" who the criminal is using to mask his true obsession. Jack and Will go to Minnesota to investigate.
Will and Jack visit the home of the latest victim's family. Her parents are distraught, but hold on to the frail hope their daughter Emily is still alive. Will asks the parents if their cat has been acting odd since the abduction. When she disappeared, Emily was due to come home to look after the family cat. When Will finds out the cat was acting normally, Will knows Emily fed him before the crime and concludes the abduction occurred at the family house. When Will enters Emily's bedroom with her father, he finds a deceased Emily lying tranquilly in her bed. Her father drops the cat. The killer brought her corpse back.
Will uses his powerful imagination to get inside the mind of the killer and see exactly how the crime took place. The killer bore down on Emily's ribs much like a deer would to stun its prey and then proceeded to strangle her. Before Will can finish his process, Beverly Katz, a forensics specialist, interrupts him. She's found antler velvet in two of the dead girls' wounds. Will tells her that antler velvet promotes healing and he thinks the killer must have placed it in her wounds as a means of undoing as much of his crime as he could. It's why he's brought her back. For some reason, whatever he did to the other seven victims, he just couldn't do to her.
Later, when Will's driving at night, he comes across a stray dog. Will takes the dog home with him, introducing the animal to the other eight canines he's taken in. Sleeping fretfully, Will has a nightmare that Emily's corpse is sleeping right beside him. He snaps out of the dream in a cold sweat. His work as a profiler is starting to take a real toll.
Jack's concerned that Will's becoming somewhat unstable. Will admits this killer has tested everything he knows about criminal profiling. Will fears the killer will act again soon. Will's colleague Alana Bloom tells Jack she thinks Will keeps a large amount of fear suppressed while on the job and suggests Jack keep him away from that kind of environment. But Jack knows the stakes are already too high.
In the autopsy room, forensics specialist Beverly Katz reveals metals traces from the crime scene. Will realizes what the metal was used for - the killer mounted the victim on hooks. When one of the specialists mentions he took her liver out and then put it back, Will realizes the worst. The killer's a cannibal. There must have been something wrong with the meat. One of the examiners says the victim had liver cancer.
Hoping to help Will cope with the stresses of chasing the killer, Alana refers Jack to her mentor, Dr. Hannibal Lecter, an expert in the field of psychology. Jack brings Hannibal to Quantico to brief him on the case; it is here that Lecter first meets Will. Hannibal notices Jack is uncomfortable with eye contact; his burgeoning neurosis is peeking through. It's a somewhat rocky start, but nevertheless, Hannibal is confident he can help.
Another body turns up in a Minnesota field, naked and impaled on the antlers of a deer. The police are quick to identify the serial killer as the "Minnesota Shrike," a play on the bird known for impaling its prey on makeshift branches or wire as a means of saving their food for later. It's clear the killer is mocking Will and Jack. Whoever's committing these murders must have a daughter of similar age to the victims, whom he can't stand the thought of letting go. It's his "golden ticket." Elsewhere, in a kitchen far removed from the crime scene, Dr. Hannibal Lecter calmly cuts up a pair of human lungs and prepares them for consumption. Back at the scene of the crime, Will thinks he's had a breakthrough.
Although all three planned to meet, Dr. Lecter shows up at Will's hotel without Jack, whom he claims has been deposed to court. Hannibal's brought breakfast for them both. Lecter tries to break through Will's tough exterior, but Will doesn't budge. Hannibal asks about the most recent crime. Will explains to Dr. Lecter his thoughts regarding the murderer, that he thinks the killer views one of these victims as a "golden ticket" and may have a daughter of his own that's a similar age. Playing along, Hannibal continues to psychoanalyze Will.
When Will and Hannibal visit a construction site in connection to the latest murder, Will finds something odd in one man's file. His name is Garrett Jacob Hobbs, a pipe threader. In addition to some recurring absences, they notice that there's also no address on his letter of resignation. As they transport the files into Will's car, Hannibal purposefully drops one of the boxes and causes a mess. Will and the office secretary clean it up, while Hannibal sneaks back into the office to do some snooping of his own.
In the office, Hannibal uses a tissue to pick up the phone, and calls the residence of Mr. Garrett Hobbs. His daughter answers the phone; she's eerily similar in size and look to the serial killer's previous victims. Garrett, nervous, gets on the phone and speaks to Dr. Lecter. Under the pretenses of courtesy, Hannibal informs Mr. Hobbs that, "they know."
The intensity of the case is starting to break Will down. He pops a few aspirin before approaching the house of Garrett Jacob Hobbs, now the lead suspect in the case. Hannibal follows Will at a distance. As Will nears the door, Garrett opens it and shoves his bleeding wife outside. Will rushes to her aid as Garrett slams the door. His wife's throat has been slit, and she's bleeding out. Hannibal remains in the distance. Will rushes in, gun drawn. He fires a shot at Hobbs right as the he's slitting his daughter's throat. As she falls to the ground, Will fires six more rounds at Hobbs, killing him. Hannibal rushes in and helps stabilize the girl's bleeding. She's rushed to the hospital. When Will goes to the hospital later on to check on the girl, she and Hannibal are both sleeping, his hand holding hers.