A deadly virus, released in the year 1996, wipes out almost all of humanity; forcing survivors to live underground. A group known as the Army of the Twelve Monkeys is believed to have released the virus.
In 2035, James Cole is a prisoner living in a subterranean compound beneath the ruins of Philadelphia. Cole is selected to be trained and sent back in time to find the original virus, in order to help scientists develop a cure. Meanwhile, Cole is troubled by recurring dreams involving a foot chase and shooting at an airport.
Cole arrives in Baltimore, 1990, not 1996 as planned and is arrested, then hospitalized at a mental hospital on the diagnosis of Dr. Kathryn Railly. There he encounters Jeffrey Goines, a mental patient with fanatical environmentalist and anti-corporatist views. Cole is interviewed by a panel of doctors where he tries to explain that the virus outbreak has already happened and that nobody can change it.
After an escape attempt, Cole is sedated and locked in a cell but disappears moments later; waking up back in 2035. Cole is interrogated by the scientists who play a distorted voicemail message that asserts the association of the Army of the Twelve Monkeys with the virus. He is also shown photos of numerous people suspected of being involved, including Goines. The scientists offer Cole a second chance to complete his mission and send him back in time. Cole accidentally arrives at a battlefield during World War I, is shot in the leg and then suddenly transported to 1996.
In 1996, Railly gives a lecture about the Cassandra complex to a group of scientists. At the post-lecture book signing, Railly meets Dr. Peters who tells her that apocalypse alarmists represent the sane vision while humanity’s gradual destruction of the environment is the real lunacy.
Cole arrives at the venue after seeing flyers publicizing it, and when Railly departs, he kidnaps her and forces her to take him to Philadelphia. They learn that Goines is the founder of the Army of the Twelve Monkeys before they set out in search of him. When they confront Goines, he denies any involvement with the group and says that, in 1990, Cole originated the idea of wiping out humanity with a virus stolen from Goines’ virologist father.
About to be apprehended by police, Cole is transported back to 2035 where he reaffirms to the scientists his commitment to his mission. But when he finds Railly again in 1996, he tells her he now believes himself crazy as she had suggested all along. Railly, meanwhile, has discovered evidence of his time travel, which she shows him; believing he is insane. They decide to depart for the Florida Keys before the onset of the plague.
On their way to the airport, they learn that the Army of the Twelve Monkeys was not the source of the epidemic; the group’s major act of protest is releasing animals from a zoo and placing Goines’ father in an animal cage. At the airport, Cole leaves a last message telling the scientists that in following the Army of the Twelve Monkeys they are on the wrong track, and that he will not return. Cole is soon confronted by Jose, an acquaintance from his own time, who gives Cole a handgun and ambiguously instructs him to follow orders.
At the same time, Railly spots Dr. Peters and recognizes him from a newspaper photograph as an assistant at Goines’ father’s virology lab. Peters is about to embark on a tour of several cities that match the locations and sequence of the viral outbreaks.
Cole forces his way through a security checkpoint in pursuit of Peters. After drawing the gun he was given, Cole is fatally shot by police. As Cole lies dying in Railly’s arms, Railly suddenly begins to scan the crowd around her; seemingly looking for something she knows must be there. Railly finally makes eye contact with a small boy—the young James Cole witnessing the scene of his own death, which will replay in his dreams for years to come. Peters, safely aboard the plane with the virus, sits down next to Jones, one of the scientists from the future, who comments that her job is “insurance.”