Cole and Ramse mend their broken friendship while on the run from the Army of the 12 Monkeys. And in the year 2043, Railly and Jones navigate an uncertain future as Deacon and the Twelve command the Temporal Facility.

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.

Jones turns to Ramse for help getting Cole and Cassie back from 1944; Jones visits old Jennifer Goines to explore the true nature of time.

In the present, Cassie and Jennifer Goines run from the 12 Monkeys; in 2044, Cole and Ramse face off against Deacon.

Cole comes face to face with the Witness, the phantom behind the Army of the 12 Monkeys as Cassie's hallucinations undergo a chilling evolution.

Cassandra Railey goes back to 2020 on a mission to kill Dr. Katarina Jones. Followed by James Cole to stop her from this mission, they find themselves stuck in a time loop.

In 2016, Jennifer Goines has taken her power into her own hands and forms The Hyenas, a band of crazy compatriots, to take on the 12 Monkeys' organization.

Cole's loyalty is tested when Ramse and Railly go rogue and embark on an unsanctioned mission into 1961 East Berlin in the hopes of finding an unscrupulous German doctor who knows the location of The Witness so they can kill him.

As the temporal facility gets closer to destruction, Cole goes to 1957 to save humanity while everyone else looks for Titan, the stronghold of the Witness.

Cole and Cassandra search for the primary in 1957 to prevent the paradox , while in 2044, Ramsey, Deacon and the daughters try to find titan to kill the witness.

Cole and Railly adjust to the past, but a mysterious woman with apocalyptic visions gets them to do the unthinkable to save the world.