Crash: Mind over Mutant is the sequel to Crash of the Titans and continues the storyline of its predecessor.

The Titans from the previous game have broken free from Dr. Cortex' control and have settled down on various places on Wumpa Islands. But Cortex has teamed up with Nitrus Brio to develop a device which can control both the Bandicoots and the Titans. Now Crash and his friends must find out where Cortex is hiding and stop him before he can act out his devious plan.

Crash can use a light-powered attack to defeat smaller enemies, but for bigger enemies, a more high-powered attack is needed. Crash can also block and dodge attacks. Just like in Crash of the Titans, Crash can take control of the Titans which he encounters. But this time he can take the Titans with him and use them when he needs it. As Crash defeats more and more enemies, he can upgrade both his own attacks and the attacks of the Titans in his possession.

For the Nintendo DS, a different 3D game was released.