In 2035, twenty-nine years after a virus killed 99 percent of the global human population, James Cole is a prisoner in a compound underneath the ruins of Philadelphia. He is selected by scientists for a mission to travel to 1996 and collect information on the original strain of the virus so a cure can be developed. Cole experiences recurring dreams of a childhood experience in which he saw a man being shot in an airport terminal. Upon being sent back in time, Cole arrives in Baltimore in 1990, not 1996 as planned. He is arrested and committed to a psychiatric hospital on the diagnosis of Dr. Kathryn Railly. He encounters fellow inmate Jeffrey Goines, an outspoken critic of consumerism. Cole tells the hospital doctors he is searching for the Army of the Twelve Monkeys, the group that unleashed the virus in 1996, which is the past. During an escape attempt aided by Jeffrey, Cole is abruptly returned to the future. The scientists attempt to send Cole back to 1996, but he briefly arrives on a World War I battlefield, where he encounters José, another inmate from the future, before being shot in the leg. In 1996, Railly gives a lecture on the Cassandra Complex where she briefly encounters Dr. Peters, who mentions the destruction of the environment by humanity. She is kidnapped in her car and told to drive to Philadelphia. The kidnapper turns out to be Cole. Railly offers him medical help and extracts the bullet from his leg. His investigation leads them to Jeffrey, which they discover is the leader of the Army of the Twelve Monkeys and the son of renowned virologist Dr. Leland Goines. Cole is abruptly returned to the future. Railly is told by police that the bullet from Cole's leg was from before the 1920s, which prompts her to identify Cole in a battlefield photograph from World War I that she's gathered during her research. She urges Leland to secure his lab against access by his son. Leland shares his intention to improve the lab's security with his assistant, Dr. Peters. Cole arrives in 1996 again and finds Railly. He tells her he believes himself delusional, while she says she's not sure any more. Railly leaves a voicemail on a number Cole says was given to him by the scientists. Cole tells her he has already heard her message, played to him by the scientists in the future. Cole and Railly decide to spend the following days together at the Florida Keys. On their way there, they learn that the Army of the Twelve Monkeys is an animal rights organization led by Jeffrey, and their graffiti "we did it" refers to liberating animals from the Philadelphia Zoo, not releasing the virus. At the airport, Cole records a message on the voicemail number, saying the Army of the Twelve Monkeys is a false lead and that he's not coming back. Railly comes across Dr. Peters at the airport and recognizes him through a newspaper photo alongside Leland. Cole comes across José, who tracked him down after his last message, and hands him a gun. Railly informs Cole of Peters, and Cole attempts to shoot him, but is shot dead by police. As Cole dies in Railly's arms, she makes eye contact with a young boy witnessing the scene. Peters boards his flight and takes a seat beside Jones, one of the scientists who orchestrated Cole's mission. Outside the airport, the young boy who observed the shooting, James, watches the airplane take off.

Spencer Reinhard, an art student seeking excitement or tragedy for inspiration, is given a tour of Transylvania University library's rare-book collection; his eye is drawn to a rare first edition of John James Audubon 's Birds of America. He and his friend Warren Lipka, a rebellious student on an athletic scholarship at the University of Kentucky, discuss the possibility of stealing it and other rare books. They note that the collection is guarded by only one librarian, whom they believe they could easily overpower before stealing the books and escaping via the staff elevator. Warren travels to Amsterdam to meet black-market buyers who express interest, informing Spencer they could make millions. They later enlist the help of two friends: Eric Borsuk to provide logistics and Chas Allen as the getaway driver. They make an appointment for a private viewing of the collection in order to gain access to the room, and arrive disguised as elderly businessmen; but they abort the heist when Warren sees multiple librarians in the room. Spencer wants to abandon the plan, but Warren persuades him and the others to try again the next day. Spencer acts as a lookout as Warren and Eric, without disguises, enter the library. Warren clumsily uses a stun gun on the librarian, making Eric help restrain her. They blunder to the exit, dropping The Birds of America, but escape with two books. The group travels to Christie's auction house in New York to get the authentication of value Warren said the Dutch buyers required. Spencer is told he has to return the next day and leaves his cell phone number with an assistant. Chas berates Spencer for using a phone number that can be identified as his, and they return to Lexington with the books. Shortly after, Spencer realizes the police will also be able to trace the email address they used to make the appointments with Christie's and the library; the FBI eventually does, and they are arrested. In documentary interviews with the real-life thieves filmed years after they are released from prison, they express regret. Spencer suspects Warren lied about going to Amsterdam in order to convince the others to partake in the heist. Eric and Chas now live in California as a writer and a fitness coach, respectively; Warren studies filmmaking in Philadelphia; and Spencer lives in Lexington as an artist.