In the year 2035, convict James Cole reluctantly volunteers to be sent back in time to discover the origin of a deadly virus that wiped out nearly all of the earth's population and forced the survivors into underground communities. But when Cole is mistakenly sent to 1990 instead of 1996, he's arrested and locked up in a mental hospital. There he meets psychiatrist Dr. Kathryn Railly, and patient Jeffrey Goines, the son of a famous virus expert, who may hold the key to the mysterious rogue group, the Army of the 12 Monkeys, thought to be responsible for unleashing the killer disease.

Born under unusual circumstances, Benjamin Button springs into being as an elderly man in a New Orleans nursing home and ages in reverse. Twelve years after his birth, he meets Daisy, a child who flits in and out of his life as she grows up to be a dancer. Though he has all sorts of unusual adventures over the course of his life, it is his relationship with Daisy, and the hope that they will come together at the right time, that drives Benjamin forward.