27 years after a virus wipes out most of humanity, scientists send James Cole back to 2015 to stop the plague from ever happening. Cole's only lead is 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.

Cole's search for the location of the virus leads him to 2014, and to a devastating moment in Dr. Railly's life involving a dangerous outbreak in Haiti.

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.

When the tragic events of the Night Room create an alternate reality in 2043, Cole risks his future.

Cole, Dr. Railly and Aaron strive to stop the virus from being deployed as a bio-weapon in Chechnya.

The Core that powers the time machine is fading. To get Cole back from the past, Jones must convince her former colleagues at the military operation "Spearhead" that her mission is worth saving.

Cole finds himself in 2017 at the height of the plague. Out of options, Jones faces an impossible choice to replace the Core.

Forces come to a head when Ramse does what it takes to protect his newfound family, leaving Cole to deal with the aftermath.

Cole splinters to Tokyo, 1987 in a last chance effort to stop the Army of the 12 Monkeys.

With Cole dying from the effects of time-travel, Railly must find the one person who can save him.

Cole and Railly attempt a final confrontation with their closest enemies, while Jones faces a new threat to all that she's accomplished.