Crash Twinsanity is the fifth mainline series game of the Crash Bandicoot series where Crash and the villain Cortex are forced into partnership. Each character occupies the same screen but they run along on different planes. Crash's gameplay is mostly the same as before, he can still do his trademark spin attack, double jump and body slam moves. The originality comes in his duo with Dr. Cortex, as he can throw him to places he can't reach himself or use him as a hammer to slap enemies. The consistent conflict between both heroes causes many funny situations.

The story is set three years after the events of Crash Bandicoot: The Wrath of Cortex, where the villainous Doctor Neo Cortex and the mighty Uka Uka were left stranded in the Antarctic sea. In this game's story, N. Sanity Island comes under threat by a sinister duo called The Evil Twins, forcing Crash Bandicoot to reluctantly team up with his arch nemesis and creator, Doctor Neo Cortex, whom the twins seek revenge against.