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.

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Cole returns to the year 2015 to gather knowledge from a patient inside a mental institution. Jones believes that the 12 Monkeys are somehow involved in the pandemic that wiped out the population of Earth, thus making Cole's attempt to extract the information from the patient, imperative. Dr Railly feels that her intervention in Cole's case has given her incentive to continue to help him in his mission, much to Cole's compliance.

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Cole is led to Haiti in 2014, where a dangerous outbreak proved to be a devastating moment in Dr. Railly's life.

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

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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.

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After the events in the night room, Cole automatically returns to 2043 and finds that the timeline has been altered. He meets Jones, who has no idea who he is. In this timeline, the time transporter is not functioning but a blood tests confirms that they had met previously. A database check also reveals that Cassie was killed in 2015, likely the event that caused the change. He finds that Ramse is in charge of the facility and after some persuasion, he agrees to send Cole back to 2015. To set things right, he has to keep Cassie from being killed.

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

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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.

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

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Forces come to a head when Ramse takes measures to protect his newfound family, leaving Cole to deal with the fallout.

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

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

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Cole and Cassandra try for a final confrontation with the Witness, while Jones faces a new threat to the mission.

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