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 along with a brilliant psychiatrist — Dr. Hannibal Lecter.

Will Graham, now an official special investigator with the FBI, helps Jack Crawford and the BAU unit search for a murderer who buries his victims alive to use as fertilizer. Tabloid journalist, Freddie Lounds, sets her sights on Will.

Determined to give Abigail closure after waking up from her coma, Will and Hannibal take her back to the scene of her father's crimes.

A string of family murders takes place and Will determines they were conducted by each of the families' missing children, who were abducted and brainwashed into killing their old families for their sinister "new family." Against Alana's recommendation, Hannibal checks Abigail out of the hospital for some frightening psychiatric practices that ultimately align her loyalty with him.

Will Graham and the BAU team track a serial killer whose bloody ritual includes cutting the victims' back flesh and stretching it to look like angel wings. Returning to the field weighs heavily on Will's psyche and Hannibal tries to drive a wedge between Will and Jack. Meanwhile, Jack Crawford's wife Bella pulls away from him and begins seeing Hannibal as her therapist, in an effort to come to terms with the fact she is dying. Beverly tries to connect with Will on a more personal level.

Jack and Alana are contacted by a former colleague, Dr. Chilton, who believes he has The Chesapeake Ripper in custody, but then one of his patients commits a murder that matches The Ripper's profile. The team determines the Ripper was a surgeon and is still at large when Jack's former protege Miriam becomes the next victim. Jack copes with her loss and the prospect of losing his wife by opening-up to Hannibal.

When the BAU investigates a murder involving organ removal Jack believes that the Chesapeake Ripper may have resurfaced, but Will determines that the victim's murder is the result of illegal organ harvesting accident. Meanwhile, Will suffers from nightmares where he is Abigail's father, and Hannibal slowly starts to seduce Alana Bloom and begins to visit his own therapist, Dr. Bedelia Du Maurier.

The BAU investigates a murder in which the killer exposes the victim's vocal cords to literally play them like a cello. Meanwhile, Hannibal discovers that the killer, Tobias, murdered the victim as an attempt to gain Hannibal's attention but then makes an attempt to take Lecter's life. Will is driven to distraction by strange noises in his head and turns to Alana, in a romantic way, seeking peace and stability. Hannibal describes his relationship with Will to his therapist, Dr. Bedilia Du Maurier.

The BAU team hunts a serial killer who digs up his victims, creating a totem pole of their bodies as a macabre trophy. When Nick Boyle's body is found, Jack and Alana question Abigail about his death. The resurrection of Nick's body enlightens Will to some of Abigail's secrets and Hannibal convinces Will to keep some of his own. Attempting to assert independence, Abigail agrees to write a book with Freddy Lounds and in the process, reveals her biggest secret to Hannibal.

The BAU investigates a murder in which two victims' faces are similarly mutilated; given a "Glasgow Smile." For the first time, Will contaminates a crime scene thinking he committed the first murder and an MRI shows he suffers from Advanced Encephalitis. But Hannibal intimidates the attending physician, Dr. Sutcliffe, into telling Will he's okay. Meanwhile, the team doubts Will who says, while revisiting the crime scene alone, he saw a mysterious, "dead-looking" woman who may be involved. With his fears fed by Hannibal, Will returns to Dr. Sutcliffe for more mental health tests, when the doctor is murdered.

When Dr. Gideon escapes from police custody, he seeks to kill psychiatrists who have profiled him. Will and the BAU team try to track him down by following Freddie Lounds' blog before Gideon can get to Alana. Hannibal misleads the BAU team in order to put Will in the same room as Gideon, and Jack questions Dr. Chilton regarding Gideon's escape.

After Georgia Madchen dies in an explosion, Will asserts that the copy cat killer is still alive. The BAU team links Abigail to the Minnesota Shrike victims and plan to arrest her only to find Will has checked her out of the hospital. Will's hallucinations intensify, causing him to lose Abigail in Minnesota. Meanwhile, Hannibal's subtle manipulation convinces Jack that Will is capable of murder. Hannibal makes an astonishing admission to Abigail.

When Will returns from Minnesota without Abigail, Hannibal turns Will in and Jack and the BAU team find strong evidence of Will having killed not only Abigail but additional evidence points to all the murders of the Copy Cat Killer. Jack and Alana begin to accept that Will is indeed capable of murder. Will is arrested and in a desperate attempt to escape, breaks his own thumb to slip the handcuffs and frees himself. Will takes Hannibal back to Minnesota to clear his name and to prove Hannibal's guilt. But before he can, the situation takes another ugly and unexpected turn.