Using a dangerous and untested method of time travel, Cole arrives from a post-apocalyptic future in the present day. His mission is to locate and eradicate the source of a deadly plague that will eventually decimate 93.6% of the human race.
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 time travel to New York during World War II to track down a dangerous member of the Twelve.
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.
In the present, Cassie and Jennifer Goines run from the 12 Monkeys; in 2044, Cole and Ramse face off against 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.
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.
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.
Ramse and Railly go on an unsanctioned mission to 1961 East Berlin, and 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.
27 years after a virus wipes out most of humanity, scientists send James Cole back to 2015 to stop the plague from ever happening. Cole's only lead is virologist Dr. Cassandra Railly, who knows the dangerous source of the outbreak.
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.
Cole's search for the location of the virus leads him to 2014, and to a devastating moment in Dr. Railly's life involving a dangerous outbreak in Haiti.
A fight for the future ensues when a dangerous band of marauders hunting for Cole and Ramse threatens the mission to save the past.
Cole and Dr. Railly face off with the Army of the 12 Monkeys when both discover the Night Room – an off-site, black ops lab that houses the virus that will one day destroy the world.
When the tragic events of the Night Room create an alternate reality in 2043, Cole risks his future.
Cole, Dr. Railly and Aaron strive to stop the virus from being deployed as a bio-weapon in Chechnya.
The Core that powers the time machine is fading. To get Cole back from the past, Jones must convince her former colleagues at the military operation "Spearhead" that her mission is worth saving.
Cole finds himself in 2017 at the height of the plague. Out of options, Jones faces an impossible choice to replace the Core.
Forces come to a head when Ramse does what it takes to protect his newfound family, leaving Cole to deal with the aftermath.
Cole splinters to Tokyo, 1987 in a last chance effort to stop the Army of the 12 Monkeys.
With Cole dying from the effects of time-travel, Railly must find the one person who can save him.
In the apocalypse of 2163, a desperate Cole searches for Titan. Meanwhile, a captive Railly is faced with an impossible choice as the 12 Monkeys await the arrival of The Witness.
While searching for Jennifer Goines in post-WWI France, Cole and Jones encounter a dangerous group of time- travelers - the Guardians.
Bonds of trust are tested when Ramse returns to the facility with an old enemy held captive. How far will Cole and Jones go for the answers they need?
Ramse and Cole splinter to 2007 expecting either a trap - or a final chance to kill The Witness. But when Cole discovers a heartbreaking truth, he’ll discover that the mission was both.
Out of time and in need of answers, Jennifer and Deacon are sent to 1989 to steal a sacred document. Can Railly and Cole get to the Word first before it reveals the one secret they want kept?
In 1953, Cole and Railly reunite with Agent Gale at the birth of the Army of the 12 Monkeys.
Cole and Railly find themselves at opposite ends of an unspeakable decision. Jones grows suspicious while Railly turns to an emotional ally for advice. All hell breaks loose during a massive fire-fight.
Friends and enemies converge in Victorian London to await the arrival of The Witness. Cole and Railly lead their pursuers on a manhunt through time.
Cole and Railly finally learn the heart-breaking life story of the man who calls himself The Witness, the reason why he wants to destroy time and all reality is revealed.