Cole and Ramse repair their broken friendship while on the run; Railly and Jones navigate an uncertain future in 2043.
When an attempt to destroy the virus changes the future, Cole finds himself stranded in 2016 with an unstable Jennifer Goines, who may or may not be his key to getting home. Meanwhile, Jones and Railly must deal with both the consequences of the changed timeline and the temporal facility's newest prisoner -- Ramse.
Despite the growing tension between them, Cole and Cassie time travel to New York during World War II to track down a dangerous member of the Twelve.
When Cole and Cassie are stranded in 1944, Jones must turn to the person she trusts the least to bring them home -- Ramse. For Ramse, this mission will give him a chance to atone for his sins -- but can he mend the broken relations between Cole and Railly? Meanwhile, Jones visits Old Jennifer Goines to explore the true nature of Time - and the Twelve’s method to destroy it.
In the present, Cassie and Jennifer Goines run from the 12 Monkeys; in 2044, Cole and Ramse face off against Deacon.
Cole's partnership with Ramse is put to the test when they travel back to the 1970s to try to prevent the Twelve from murdering a disturbed Vietnam veteran with a connection to the Witness.
Cole faces the Witness as Cassie's hallucinations evolve; deadly visitors from the past arrive when the time machine malfunctions and begins tearing apart time and space.
Jones comes to the disheartening realization that time travel is humanity's true enemy and that as its architect she needs to be stopped, and so she sends Railly back to the year 2020 with orders to undo all of it.
Jennifer Goines takes her power into her own hands in the year 2016 when she forms the Hyenas, a band of crazy compatriots, to take on the 12 Monkeys. With the help of Cole, an elaborate plot is uncovered to reacquire the virus.
Ramse and Railly go on an unsanctioned mission to 1961 East Berlin, and have murder on their minds as they search for an unscrupulous German doctor who knows the location of "The Witness".
With the temporal facility on the verge of destruction, Cole and Jones find themselves in the middle of a coup. After a violent encounter ends in an unexpected tragedy, Cole is sent back to 1957 in a last-ditch effort to save humanity while the rest embark on a caravan across the apocalypse to find Titan -- the stronghold of the Witness.
Cole and Railly attempt to stop the final paradox in the past while Ramse, Jennifer and Deacon struggle to survive the apocalypse in a last ditch effort to find the Witness.
Cole and Railly have finally found peace living in the past. When a mysterious woman with apocalyptic visions of the future tells Cole it's not over, he must do the unthinkable to save the world... and the woman he loves.