The trail of a mysterious organization called the “Army of the 12 Monkeys” leads Cole to a mental institution in 2015, where a patient holds the key to the plague that destroys the world. Meanwhile, despite warnings that her involvement may disrupt the course of history, Dr. Railly risks her life to help him.
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.
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.
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.