- California Doubling: While the film is set in the Midwest, it was actually shot in Cape Town, South Africa.
- Fake American: Irish Eoin Macken and South Korean Lee Joon-gi play Americans Doc and Commander Chu, respectively.
- Fatal Method Acting: One of the film's crew members, Ricardo Cornelius, was crushed to death by a Humvee while on set.
- On-Set Injury: Olivia Jackson, Milla Jovovich's stunt double, crashed into a camera crane during a motorcycle stunt. The accident left her in a coma for two weeks, and among Jackson's injuries were cerebral trauma, a crushed face, a severed artery in her neck, a paralyzed arm, several broken ribs, a shattered scapula, a broken clavicle, torn fingers with a thumb that needed to be amputated, and five nerves torn out of her spinal cord. The paralyzed arm also later needed to be amputated. Jackson later successfully sued the stunt coordinators for negligence.
- Real-Life Relative: The movie was directed by Jovovich's husband, Paul W.S. Anderson, and her real life oldest daughter, Ever Anderson, played Alicia Marcus/Red Queen.
- Recycled Script: As if the film having yet another Laser Hallway sequence as a part of its climax wasn't blatant idea recycling already, Alice once again has a showdown with Dr. Isaacs in said hallway. Also, there are once again yet more clone shenanigans with Alice and Dr. Isaacs.
- Role Reprise:
- Ali Larter reprises her role as Claire Redfield, a role she last played in 2010's Resident Evil: Afterlife.
- Iain Glen returns to play Dr. Alexander Isaacs in the flesh for the first time since 2007's Resident Evil: Extinction.
- What Could Have Been:
- Li Bingbing was set to return as Ada Wong, but she had to pull out of production due to schedule problems. Conversely, Sienna Guillory wanted to continue playing Jill Valentine, but the producers never called her or any other cast member from the previous film.
- Jovovich's daughter Ever was supposed to play the young Alicia with no dialogue. However, she was asked to stand in for the Red Queen during some tests, and she did so well that the producers decided to cast her in that role.
- According to Jovovich herself, Alice was supposed to die in the end of the film, but the change has been made at the last minute to ensure her survival.
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