After nearly a year searching for the Primary, tensions are running high between Cole and Railly as the date of the final paradox draws near. They are working in a factory--Cole as a laborer, Railly as a secretary--and still have not found the Primary. After arguing with Railly, Cole has a drink with his coworker Charlie, whose wife is dying of cancer. Charlie advises him to take a chance on happiness with Railly before time runs out.
Railly learns that a new work crew will be brought on at the factory the next day, and suggests that Cole investigate them for the Primary. Among them, Cole notices one man, Reginald, who behaves erratically. Railly checks his employment file and finds a picture of a monkey on the back. Cole confronts Reginald and prepares to kill him. However, Reginald confesses he had been paid to act strangely by someone else.
Back at the factory, Railly confronts a woman with a gun and a box--Charlie's wife, Melinda. Charlie appears and disarms Railly, revealing himself as a Messenger. Cole arrives, and Charlie explains that he paid Reginald to trick Cole. He fell in love with Melinda--his target and the final Primary--and couldn't bring himself to kill her. Melinda opens the box, revealing a knife made of her bone, and urges Charlie to paradox her so they can be together forever in the Red Forest. Charlie does so, causing an explosive temporal paradox that knocks out Cole and Railly.
Cole visits a comatose Railly in the hospital. He says farewell, kisses her, and leaves.
Railly awakens from her coma. The doctors tell her she has been out for over six months. She goes to her and Cole's room at the Emerson Hotel, finding it completely empty and Cole gone.
Railly is working as a nurse and training to qualify as a doctor. She finally tracks down Cole, finding that he bought the house of cedar and pine she had seen in her visions, and is living in it and repairing it. She realizes the 12 Monkeys always planned for her to come there. She and Cole argue over the failure of their mission and what they should do with their lives next. They come to terms with their feelings for one another and make love.
After a year of searching, José Ramse, Marcus Whitley, Hannah Jones, and Adler arrive at Titan and confront a masked figure dressed like the Witness. All four are killed by the figure's confederates. Jennifer Goines and the remainder of the Daughters stay behind after Jennifer undergoes a challenge to her leadership.