27 years after a virus wipes out most of humanity, scientists send a man (James Cole) back to 2015 to stop the plague from ever happening. Cole's only lead is a virologist (Dr. Cassandra Railly), who knows the dangerous source of the outbreak.

The trail of a mysterious organization called the “Army of the 12 Monkeys” leads Cole to a mental institution in 2015, where a patient holds the key to the plague that destroys the world. Meanwhile, despite warnings that her involvement may disrupt the course of history, Dr. Railly risks her life to help him.

A fight for the future ensues when a dangerous band of marauders hunting for Cole and Ramse threatens the mission to save the past.

Cole and Dr. Railly face off with the Army of the 12 Monkeys when both discover the Night Room –- an off-site, black ops lab that houses the virus that will one day destroy the world.

After the tragic events of the Night Room create an alternate reality in 2043, Cole risks his future to save Dr. Railly.