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 travel to 1940s New York during World War II to track down a dangerously seductive member of the Twelve who's plotting an assassination.
Jones reluctantly places her trust in Ramse to bring Cole and Cassie safely home after they get stranded in the year 1944. As Ramse looks forward to this chance to atone for his sins, Jones explores the true nature of time with old Jennifer Goines.
Cassie and Jennifer must work together to save the future, while Cole makes a surprising move with 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.
Cassie is sent to 2020 by Jones with one mission: Kill the younger Jones and prevent time travel from ever happening.
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.
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 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.