The game is an action role-playing game described by Square Enix as a "cinematic action RPG". Director Hajime Tabata noted that the gameplay and plot are intertwined due to a newly introduced ability called "Overdive," an ability that lets the player switch bodies with one of their team members, allowing them to control friendly NPCs. Teammates can be ordered either to target specific enemies or to defend themselves in combat. The player is able change their controlled character in real-time, intermixed with their combat actions. The game is played over-the-shoulder, comparable to games such as Resident Evil 4, Dead Space and the Mass Effect series. An array of different costumes will be available for Aya to choose from throughout the game, but only after they are unlocked by completing the game in various difficulty modes. Clothing in the game deteriorates due to battle damage, revealing Aya's skin to various degrees.

The game takes place in Manhattan, New York City ten years after the events of Parasite Eve II. The player takes on the role of Aya Brea, and must fight against mysterious "Twisted" creatures threatening the city.