Stuntwoman Olivia Jackson was involved in a motorcycle crash during filming. The dangerous stunt involved her driving a motorcycle towards a camera mounted on a crane, while she wore no helmet as the shot required her not to. The crane malfunctioned and didn't move out of the way in time. Noticing this, she tried (and failed) to block it with her arm. She received several serious life threatening injuries including a twisted spine, broken discs, brain bleeding, shattered scapula, nerves torn, leaking cerebral fluid, degloved face (which is when facial skin is ripped off to reveal muscle tissue and teeth), shattered eye socket which had to be put together with tweezers, cheekbone shard stabbing her ear drum, fingers torn from her hand, an entire bone ripped out of her arm. Her left arm, which suffered these injuries, was injured so badly it had to be amputated. She was put into a medically induced coma for 17 days to perform all of the surgeries. Paul W.S. Anderson was so devastated by the accident that he nearly quit the project, while Milla Jovovich visited Jackson in the hospital and brought her flowers. Jackson sued (and won) the production company for the workplace injuries, as she was initially only compensated $33,000 for the injuries.
During filming in South Africa, an improperly secured Humvee slid off of a rotating platform, crushing crew member Ricardo Cornelius against a wall. He was rushed to the hospital and placed on life support, but he died a few hours later. It was the film's second on-set accident, and the only fatal one. The film is dedicated to his memory.
Megan Charpentier had outgrown the role of the Red Queen, which she previously played in Resident Evil: Retribution (2012), and was recast with Milla Jovovich and Paul W.S. Anderson's real life daughter Ever Anderson in her feature film debut.
A TV series was supposedly in the works following the release of this final Resident Evil film, but then the idea of a reboot film was eventually announced instead. Both ideas came to fruition, with a reboot film Resident Evil: Welcome to Raccoon City (2021), and a standalone Netflix original series simply called Resident Evil (2022). Both follow their own continuity and have no connection to the Paul W.S. Anderson films.
Filming was originally scheduled to start in Fall 2013 for a September 12, 2014 release date. Filming was delayed when Milla Jovovich became pregnant with her second child.