Cole and Ramse repair their broken friendship while on the run; Railly and Jones navigate an uncertain future in 2043.

Cole gets stranded in 2016 after an attempt to destroy the virus changes the future. Jones and Railly deal with the consequences of the changed timeline.

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 and Ramse travel to 1970s New York City to prevent the Twelve from murdering a 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.

Cole has his loyalty tested when Ramse and Railly go rogue, embarking on an unsanctioned mission that sends them to 1961 East Berlin. Once there, they 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 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.