The project originated with executive producer Robert Kosberg, a fan of Chris Marker's 1962 short film La Jetée, who persuaded Marker to let him pitch a feature adaptation to Universal Pictures.

Terry Gilliam signed on to direct 12 Monkeys right after abandoning a film adaptation of A Tale of Two Cities, even though he initially felt the script for 12 Monkeys was 'too complex'.

This was only the second film Gilliam directed without writing or co-writing the screenplay, and he claimed he had not actually seen La Jetée when he made 12 Monkeys, despite the Writers Guild's skepticism over the 'inspired by' credit.

Gilliam's initial casting choices were Nick Nolte as James Cole and Jeff Bridges as Jeffrey Goines, but Universal objected; Nicolas Cage and Tom Cruise were also suggested but rejected by Gilliam.

Gilliam said he wasn't originally interested in casting Bruce Willis because of the actor's mouth, before deciding Willis evoked the right mix of strength and vulnerability for Cole.

Gilliam originally believed Brad Pitt was wrong for the role of Jeffrey Goines, but the casting director convinced him otherwise; Pitt was cast for a comparatively small salary since he was still relatively unknown at the time.

Months before filming, Brad Pitt spent weeks at Temple University's hospital in Philadelphia, visiting and studying the psychiatric ward to prepare for his role.

Principal photography ran from February 8 to May 6, 1995, and shooting on location in Philadelphia and Baltimore in winter faced weather problems and technical glitches with futuristic mechanical props.

Because the filmmakers were not allowed access to sound stages, they had to shoot in abandoned buildings and landmarks, including the Eastern State Penitentiary and Girard College for the psychiatric hospital, and abandoned motels in Camden, New Jersey.

Gilliam injured himself while horseback riding during production, yet the film still finished only a week behind schedule and stayed within its budget.

The interrogation room set was based on architect Lebbeus Woods' work 'Neomechanical Tower (Upper) Chamber'; Woods later sued Universal for using his design without permission and won a high six-figure settlement in exchange for allowing the scenes to remain in the film.

The film's score by Paul Buckmaster is built around a main theme based on Argentine tango composer Astor Piazzolla's Suite Punta del Este.

The film pays homage to Alfred Hitchcock's Vertigo, with Cole and Railly watching it in a theater, Railly recreating Judy/Madeleine's blonde transformation and coat, and Bernard Herrmann's score briefly audible.

A scene of Cole waking up in a hospital bed with scientists talking to him in chorus is a direct homage to the 'Dry Bones' scene from Dennis Potter's The Singing Detective.