As the police arrive at Dexter's house, he is obviously in shock and, either because he feels guilty that his relationship with the Trinity Killer caused Rita's death or because he is answering a question ("Sir, did you say that you called this in?") asked by one of the police officers, admits "it was me". Quinn is already suspicious about the circumstances surrounding Rita's death, considering it was not Trinity's modus operandi. Astor takes the news particularly hard, and blames Dexter for her death. Unable to reconcile, Astor decides that she wants to live with her grandparents in Orlando, and she and Cody leave Miami.

Miami Metro begin investigating a severed head in a Venezuelan neighborhood, and also find several related cases. The suspect is quickly nicknamed the Santa Muerte Killer. The FBI, unable to find Arthur Mitchell (the 'trinity killer'), follows its only other lead, Kyle Butler (Dexter's alias when interacting with Mitchell). Quinn recognizes the similarities between sketches of Kyle Butler and Dexter. Dexter finds a Department of Sanitation worker, Boyd Fowler, who is responsible for the deaths of many women. Dexter hires a nanny named Sonya to care for Harrison. Dexter eventually kills Fowler, but the crime is witnessed by Fowler's next victim Lumen Pierce (played by Julia Stiles), whom he has in captivity.

Dexter tries to care for Lumen, but she is understandably suspicious, asking Dexter if he is going to "sell her". Quinn approaches Jonah Mitchell, who is now in witness protection. He shows Mitchell a picture of Dexter and asks if it is Kyle Butler, but is interrupted by an undercover FBI agent before Mitchell can identify the picture. Quinn is suspended without pay by LaGuerta for disobeying her orders, and she continues to defend Dexter. Quinn seeks the help of a fellow officer to investigate Dexter. With Dexter's help, Deb closes in on the Santa Muerte killer, but he escapes during a hostage stand-off. Lumen tells Dexter that "there were others" with Fowler who did this to her.

Lumen asks Dexter to help her seek revenge, but he initially refuses. After Lumen continues on her own and targets the wrong suspect, Dexter teaches her the importance of knowing a person is guilty. Lumen falsely leads Dexter to believe she leaves Miami. Dexter soon learns that Lumen has remained in Miami after she shoots one of her attackers. Dexter is forced to help her cover it up, moments before Debra arrives to investigate the crime scene. She later reveals to Dexter that killing one of her attackers brought her a sense of peace, and she tearfully recognizes that it will not last, and she will have to find (and kill) the others to find that peace again. Dexter recognizes this as being her own "Dark Passenger", and decides (in part to forgive himself for failing Rita) to help her.

Meanwhile, the subplots throughout the season focus on the relationships of LaGuerta and Angel, who have made their marriage public but are having marital issues, and of Quinn and Debra who get romantically involved. When Angel gets involved in a bar fight which gets him in trouble with the Internal Affairs Dept (IAD), LaGuerta saves by helping IAD set up a sting on a different cop, Liddy (Peter Weller). Liddy develops a friendship with Quinn, both being angry about being "betrayed" by LaGuerta, and Quinn pays Liddy to investigate Dexter. Debra remains unaware that Quinn suspects her brother is Kyle Butler.

Meanwhile, Dexter and Lumen hunt the other people responsible for torturing her, including Jordan Chase (Jonny Lee Miller) and people associated with him. As Quinn's relationship with Deb deepens, he tries to call off Liddy, but by this point Liddy has taken pictures of Dexter and Lumen on Dexter's boat disposing of large plastic bags and video of them practicing for a kill. Having lost his job and convinced Dexter is a criminal, Liddy captures Dexter and calls Quinn to tell him he's got something to show him. During a struggle Dexter kills Liddy in self defense and destroys the video evidence. But he's forced to leave the body behind when Lumen is captured by Jordan Chase (who had figured out that she and Dexter were killing his accomplices). Quinn, having responded to a call from Liddy, finds Liddy's van locked, and a drop of Liddy's blood falls on his shoe. Dexter returns home to be surprised by Astor and Cody -- they want to have Harrison's first birthday party in Miami and stay with him the coming summer.

Dexter goes to confront Jordan (who has abducted Lumen) but is called away by Liddy's crime scene, where Quinn is arrested for suspicion of implication in Liddy's death. Later Dexter tracks down where Jordan is holding Lumen captive, and following a brief struggle, Dexter overpowers Jordan, and then allows Lumen to kill Jordan. Deb discovers them, though they are behind translucent plastic and she is not aware of their identities. Understanding that Lumen must be an escaped victim, Deb sympathizes, and lets them go, not seeing their faces. After Jordan's death, Lumen no longer feels the "Dark Passenger" and she leaves, leaving Dexter distraught.

Quinn visits Dexter at Harrison's birthday party, thanking him for getting him out of jail as Dexter seems to have faked a blood test to clear Quinn. Quinn and Deb appear to reconcile, as do Maria and Angel. Blowing out Harrison's birthday candle, Dexter wonders if there is hope for him -- to have a genuine relationship, to be human -- but he doubts it.