A central theme in the games is the fictional antagonistic cult religion Unitology. Its members are fanatical followers of Michael Altman, who they claim leaked information that the Earth's government was suppressing about the alien artifact called the Marker. Their primary goal is to use this Marker to bring about the so-called "convergence" or "unification". Unitologists believe that human life may have come from space, and that by worshipping the Marker they can achieve eternal life.

According to the developers, the fictional religion is supposed to represent people's illogical thinking about things they don't understand, such as the Marker and the necromorphs. Unitology has been confirmed to have its own scripture of some kind. While it is not meant as criticism of religion itself, it draws on the falsehoods and corruption that may be hidden inside one.[42]

Many players and critics have drawn comparisons between the fictional Unitology and the real-world Scientology: both have science-fiction influences, collected large funds from their members, consist of multiple ranks within their system which determine access to certain information, and host a large number of influential followers such as CEOs and celebrities. The developers have stated that these comparisons are simply meant to portray it as a secretive cult, with the name similarity causing unfortunate implications.[43][44]