In a dystopian future, humanity is forced underground by a deadly virus that has decimated 99% of the world's population. The virus's origin is believed to be tied to an eco-terrorist group known as the Army of the Twelve Monkeys. To uncover information about the disease, scientists devise time travel technology and recruit James Cole, a convict, for the dangerous mission. Cole's objective is to traverse the pre-apocalyptic world of the 1990s to locate the pure virus before it mutates, allowing scientists in his own time to study it and develop a cure.

Cole's journey through time is fraught with confusion and mistakes. Initially sent to the wrong year, he is hospitalized in a psychiatric facility where he meets Dr. Kathryn Railly, a psychiatrist, and Jeffrey Goines, an erratic patient with radical environmentalist views. Once Cole manages to convince Dr. Railly of the impending viral apocalypse, the two work together to track the path of the virus's outbreak, all the while Cole's own grip on reality wavers as he faces the surreal experience of time travel and the overwhelming pressure of his mission to save humanity from its grim fate.