Brad Pitt did 95% of his own stunts in this film according to stunt coordinator Greg Rementer. With the main exceptions being hard falls and the running scenes. He also wanted his character to grow an increasing number of bruises, cuts, and more culminating in at least three golf ball-sized lumps, but they talked him out of it.
Brad Pitt's character says that he never forgets a face but struggles to remember who The Wolf is. In real life, Pitt has prosopagnosia, a condition that impairs the ability to recognize familiar faces, including one's own face. He has said in interviews that, just as his character does, he needs to remember the context and the situation in which he has met someone in order to remember who that person is.
Director David Leitch and Brad Pitt had a long working relationship before Bullet Train (2022). Leitch has worked as Pitt's stunt double in multiple films including Fight Club (1999), Ocean's Eleven (2001), Troie (2004) and Mr. & Mrs. Smith (2005). Pitt also made a cameo in Leitch's second directorial effort Deadpool 2 (2018).
Lady Gaga was originally cast as Maria Beetle but had to drop out due to scheduling conflicts with House of Gucci (2021) and was replaced with Sandra Bullock.