27 years after a virus wipes out most of humanity, scientists send a man (James Cole) back to 2015 to stop the plague from ever happening. Cole's only lead is a virologist (Dr. Cassandra Railly), who knows the dangerous source of the outbreak.
Cole returns to the year 2015 to gather knowledge from a patient inside a mental institution. Jones believes that the 12 Monkeys are somehow involved in the pandemic that wiped out the population of Earth, thus making Cole's attempt to extract the information from the patient, imperative. Dr Railly feels that her intervention in Cole's case has given her incentive to continue to help him in his mission, much to Cole's compliance.
After the events in the night room, Cole automatically returns to 2043 and finds that the timeline has been altered. He meets Jones, who has no idea who he is. In this timeline, the time transporter is not functioning but a blood tests confirms that they had met previously. A database check also reveals that Cassie was killed in 2015, likely the event that caused the change. He finds that Ramse is in charge of the facility and after some persuasion, he agrees to send Cole back to 2015. To set things right, he has to keep Cassie from being killed.