An increasingly desperate Cole scours the year 2163 looking for the city of Titan, where a pregnant Cassie is being kept as the mother of the Witness. A mysterious figure from the future tells Cole that he must find Jennifer, who has become lost in time.
Trapped in early twentieth-century France, Jennifer attempts to make enough waves for the future to notice and come to her rescue. When Cole and Jones arrive in the year 1922 they learn that Jennifer has seen a vision of four "Horsemen of the Apocalypse" armed with a plan to end the world. Cassandra tries to see her son, and Ramse catches up with his son in 2046.
Ramse delivers an old enemy into the hands of Jones and the temporal facility, where the team quickly comes to cross purposes in how to deal with her. In 2163 a mortally wounded Deacon fights to survive both the captivity of Titan and hallucinations of his cruel father.
Cole travels with Ramse to 2007 unaware that his friend has his own mission: to murder Dr. Railly and prevent the Witness from ever being born. In the future Cassie and Duncan must fight their way out of Titan, and Jennifer turns to Olivia for answers.
Jennifer orchestrates an ambitious plan to lead a team to 1989 in order to steal the Witness's secret map of time -- risking alterations that could undo their victories and expose Cassie and Cole's secret.
Cole and Railly return to the Emerson Hotel in 1953, where they enlist the help of FBI Agent Gale to locate the origin of the Army of the 12 Monkeys. In the future Jennifer is rattled by a disturbing vision.
Cole reluctantly joins a team to 1953 to target and kill the Witness as a child, while Deacon and Jones grow suspicious that Cole and Railly are hiding something from them. Meanwhile, Cassie visits her mother in 1990.
Fugitives from their own team, Cassie and James travel to London in 1899 in the hope of locating their son. Jennifer takes desperate action to try and help her friends.
Cassie and Cole find evidence of the Witness's movements through time, including a period when he was trapped in 1891 London -- where he falls in love with a young nurse. Jennifer struggles with her visions in her imprisonment.
Cassie and Cole confront their son but find that he may be too far gone, triggering a chase through time and a final confrontation with Jones and Titan. In the future, Olivia makes her move.