Inspiration for the film, real-life multiple-personality Billy Milligan (14 February 1955 - 12 December 2014), charged with three rapes, was the first person diagnosed with multiple personality disorder to use an insanity defense by reason of that disorder, and also first to be acquitted thus. Milligan had 24 personalities, consisting of 10 Desirables: Billy Milligan, Arthur, Ragen Vadascovinich, Allen, Tommy, Danny, David, Christene, Christopher, and Adalana; and 13 Undesirables: Phil, Kevin, Walter, April, Samuel, Mark, Steve, Lee, Jason, Bobby, Shawn, Martin, and Timothy; and The Teacher, a fusion of all of the other personalities.
In order to prevent leaks, the final scene was not included in the shooting script, and also omitted from all test screenings.
When Joaquin Phoenix and the production couldn't reach a contract agreement, James McAvoy was cast in the lead.
James McAvoy broke his knuckle while filming on location in Philadelphia. He continued to film for three days before letting on that he was injured and finally sought attention at a local UrgentCare. As a result, he was forced to work with an injury on the set of Atomic Blonde (2017), as well.
M. Night Shyamalan: appears in the movie as Jai, the fast-food loving concierge of the apartment building where Dr. Fletcher works. They watch the security cameras after Barry leaves the building. Shyamalan also had a cameo in this film's predecessor, Unbreakable (2000), as an unnamed suspected drug dealer. In the next film, Glass (2019), Jai confirms that he and the dealer are the same character.
M. Night Shyamalan: [Philadelphia] This movie takes place in M. Night Shyamalan's hometown of Philadelphia. Philadelphia Phillies stickers can be seen stuck to objects throughout the film.