Crash: Mind Over Mutant is the sequel to Crash of the Titans and the seventh Crash Bandicoot series game. The game uses many of the same mechanics as its predecessor with a few changes. Rather than having twenty linear platforming levels to complete in sequence, Mind Over Mutant features eight distinct locations for Crash to explore and travel between as the story progresses. The player can complete missions given by non-playable characters and discover collectibles through the levels.

The game's story centers on the arrival of a popular technological device that puts its users under the control of the device's creators and antagonists Dr. Neo Cortex and Dr. Nitrus Brio. Crash and his magical mask friend Aku Aku are the only ones unaffected by the device, and must free their friends from its control and put an end to Dr. Cortex's plot.