Cole and Ramse try to rebuild their friendship while on the run from the Army of the 12 Monkeys in the year 2016. In 2043 Dr. Railly wakes up to a future where the enemy has seized control of the time machine, and must convince Deacon to help her.
Railly and Cole are reunited in 2016, but their efforts to destroy the virus once and for all leave Cole stranded in the past and Ramse a prisoner in the future -- where Katarina tries to come to terms with a reality that has been reshaped.
Cassie reluctantly joins Cole on a mission to 1944 to locate two Messengers who are planning to murder a scientist to bring about their future agenda. But they soon discover that the man's son, a patient at a mental institution, has a special connection to time.
Faced with an apocalyptic future Katarina reluctantly sends Ramse to 1944 to try and retrieve Cole and Railly, while undoing the Messengers' work. But after he is injured in the past, all bets are off. In 2044, Katarina goes to the aged Jennifer Goines for answers.
Cassie locates a recovering Jennifer Goines in 2016 in the hopes of finding more Primaries before the 12 Monkeys get to them first. In 2044, Cole and Ramse decide that Deacon is more trouble than he is worth.
Cole and Ramse travel to 1975 to locate a Primary before the Messengers, but face a difficult choice when they learn that the man is a serial killer. In 2016 Cassie nurses Jennifer back to health, only to encounter her late fiancé in another vision.
While Cassie experiences continuing hallucinations Dr. Jones grows suspicious that she may have brought something from the past back with her to 2044. When the time machine mysteriously overloads, visitors from the past begin showing up in the Temporal Facility.
Convinced that her own meddling with time has made the world worse, Dr. Jones sends Railly back to the year 2020 to kill Jones' own younger self. But when Cole tries to stop her, they find that they are reliving the same fateful day over and over.
The search for the final Primary leads back to 2016, where Jennifer Goines has assembled a ragtag team of the mentally unstable to hunt and kill the Army of the 12 Monkeys. Meanwhile, Railly and Ramse go in search of a man who may hold information on Titan.
Ramse and Railly reluctantly agree to join Cole on a mission to 1957, where he hopes to prevent the final paradox and save the future. But after they double-cross him, Cole must stop his friends before they can get to a German doctor who knows the location of the Witness.
As the red storm bears down on the Temporal Facility Ramse and his allies attempt to seize control in a latch-ditch attempt to reach Titan. But after Cole escapes and goes for reinforcements, the two sides clash in an all-out civil war.
After 11 months in the year 1957 Cole and Railly find themselves with no leads on the identity of the Primary. In 2044 Ramse's group draws near to the borders of Titan, and Jennifer struggles with the harsh realities of her new place in the world.
Cassandra and James find a measure of happiness as they build a new life in the 1950s, but a bizarre encounter with another Primary convinces Cole that he must take desperate action to save everyone he loves -- even at great personal cost.
