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.

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

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.

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.