A time traveler from the year 2043 arrives in the present day, searching out a brilliant virologist to find and kill a man believed to be responsible for a plague that will decimate the human race.
Cole is sent to a Philadelphia mental hospital in the year 2015 to track down a woman evidently connected with the Army of the 12 Monkeys. Meanwhile, Cassie turns to a friend for help and finds herself face-to-face with a murderer.
In search of a lead Cole travels to 2014, where Cassandra is on assignment for the CDC working on a dangerous outbreak in Haiti. But to avoid unraveling the timeline, Cole must avoid encountering her directly.
The mission to save the world is threatened when a band of marauders from Cole and Ramse's past attacks the time-travel facility, forcing Cole to take desperate actions to try and save his friends.
Cole and Railly locate the Night Room, a top-secret research facility holding the origins of Goines' virus -- only to find that it has been seized by the Army of the 12 Monkeys. Meanwhile, Ramse discovers a secret that Jones is keeping about the project.
After returning to 2043 and discovering the timeline has been altered, Cole realizes that he must save Cassie from the Army of the 12 Monkeys to put history back on the right path.
After learning that the virus is going to be deployed as a bioweapon to kill a government intelligence target, Cole travels to Chechnya to steal the virus out from under the 12 Monkeys.
In hopes of rescuing Cole from the past, Dr. Jones sends Ramses to a high-tech colony that is attempting to develop a cure for the plague. In Chechnya, Cole tries to free himself from the ruins of the attack.
Cole finds himself in 2017, with the plague running rampant across the globe. Ramse tries to protect the ones he loves when Jones determines to seize Foster's core by military force.
With the realization that they have failed to avert the future, Cassie and Cole go in search of the scientist who retro-engineered the virus for the military. In 2043 Ramse encounters a mysterious faction of women while trying to protect his family.
Cole follows Ramse to Tokyo in the year 1987, where a fateful encounter with Leland Goines may seal his fate for good. Meanwhile Ramse finds himself in prison, on the way to his own destiny.
In 2015 Dr. Railly goes to great lengths to try and save Cole's life, holding a young Katarina Jones at gunpoint to secure her help. Jennifer makes a power play inside her father's company.
Cole interrogates a former ally to learn about the group that is working against them, leading to a reformed Jennifer Goines and a confrontation with Ramse. In 2043, the head of the West 7 gang leads a mysterious group of unearthly warriors in a winner-take-all assault on Jones' facility.
