In 1996, a virus eradicated all but a fraction of humanity. You may not have noticed as it wasn't the worst thing to happen in 1996—the space invasion that occurred in major metropolitan cities worldwide was pretty bad—but it definitely happened.
Now it's 2035, and humanity lives underground while the animals rule the earth once again. The Scientists, a panel of scientists who rule the dystopian society and have a knack for on-the-nose titles, select a prisoner named James Cole for a special mission: go back in time to 1996 and gather information on the virus so a vaccine can be produced in the present.
He accepts—honestly, what else does he have going on in an underground prison?
Cole is sent to the year 1990 by mistake (guess the Scientists zigged at the temporal drift when they should have zagged). He's arrested and diagnosed by Dr. Kathryn Railly to be mentally unhealthy. At the county's mental hospital, he meets Jeffery Goines, a crazed conspiracy theorist with a large vocabulary and an even larger ego. The two get to know each other, and Goines eventually hatches a plan for Cole to escape. That plan fails, but Cole is whisked back to the future anyway.
Back in the future, the Scientists prep Cole for another go. They play him a message about the Army of the 12 Monkeys and show him pictures of those involved. Trying their luck at time travel again, they have a mild slip up that sends Cole to a World War I battlefield where he's shot in the leg. But they quickly manage to get him to 1996, so it's all good. No trench foot for Cole.
Cole kidnaps Dr. Railly after a lecture she gives at the university, and he forces her to drive him to Philadelphia. Along the way, they continually hear news stories about a boy who supposedly got stuck in a well, but Cole claims to remember the story from when he was a boy. He says little Ricky Neuman is safe and sound hiding in a barn.
In Philadelphia, Cole and Railly learn that—surprise!—Jeffery Goines is the founder of the Army of the 12 Monkeys. Cole decides to confront his mental hospital roomie, but not before Railly convinces him to let her remove that bullet from his leg. After an impromptu surgery, Cole locks her in the trunk for her protection. Yeah, we're not sure he comprehends the concept of protection either.
Cole crashes a party being held in honor of Dr. Goines, Jeffery Goines' father. Cole and Goines talk, but Goines denies being affiliated with the Army of the 12 Monkeys. In fact, he claims the idea of wiping out humanity was Cole's, based on an off-handed comment at the mental hospital. Cole attacks Goines but is chased out of the mansion by security.
Returning to the car, he releases Dr. Railly. Railly flags down the pursuing police, but before they arrive, Cole disappears. Home at last, Railly begins to chill when she sees a TV news report. Ricky Neuman is fine; in fact, he was hiding out in a barn the entire time. Cole was right.
In the future, the Scientists heap praise and a full pardon on Cole for his excellent work, but he beings to doubt the future is real. He tricks the Scientists into sending him back to 1996 to gather more information, planning the whole time to stay once he gets there.
He reconnects with Railly in Philadelphia and tries to prove to her that he is crazy, but the evidence keeps piling up that he's right about the future. Knowing they can't stop fate one way or the other, they decide to travel to Key West and just vacay until the apocalypse.
En route to the airport, they learn about Goines' true plan: he released the animals from the zoo and put his father in one of the cages. Both Cole and Railly are relieved that the Army of the 12 Monkeys are lame pranksters.
At the airport, Cole decides to call the Scientists and warn them just in case. Elsewhere, Railly runs into Dr. Goines' assistant, Dr. Peters. Remembering him from her book signing, she realizes he is the one who will release the virus. At the same time, Cole is given a gun by a fellow time-traveler and ordered to kill Dr. Peters.
Rushing through airport security, Cole attempts to kill Dr. Peters but is gunned down by police instead. Dr. Peters escapes.
Railly comforts Cole in his final moments. When the police take her away, she spies a little boy watching the horrifying events. Realizing that this boy is a young James Cole, who witnessed his own death all those years ago, she smiles sadly at him.
In the airplane, Dr. Peters sits down next to one of the future Scientists. They introduce themselves, and she tells him she is in the insurance business. And that's all, folks.