Ray Liotta was cast in the film in February 2022, but he died in May that year before he could film his scenes. Dennis Quaid replaced him, but Liotta is still mentioned in the director's "Thank You Notes" during the credits.
Demi Moore said she was nervous about filming full nudity at age 59 and felt vulnerable. But she credited co-star Margaret Qualley, who was 29 at the time of filming and portrayed a younger version of her character, with making her feel comfortable on set. Qualley also performed totally naked. Coincidentally, Qualley's mother Andie MacDowell co-starred 40 years earlier with Demi in St. Elmo's Fire: Die Leidenschaft brennt tief (1985), a career-making film for both actresses.
Margaret Qualley revealed in interviews that her breasts in the movie are not her own; they are prosthetics designed by French makeup artist Pierre Olivier Persin.
According to a making-of featurette, director Coralie Fargeat used her own arm for the shots showing the Substance needle being injected.
In the film, Elisabeth Sparkle turns 50 years old. Demi Moore, who portrays the character, was almost 60 at the time of shooting the film.