All is peaceful in Wumpa Island, Crash Bandicoot's new home. As Aku Aku sleeps and Crunch does his workout routines, Crash helps his sister Coco build another one of her gizmos. No sooner would they be rudely interrupted by none other than the usual bearded scientist, Dr. Cortex himself. Paying a visit to the bandicoots in his hovercraft, Cortex obnoxiously announces his "triumphant" return. Aku Aku volunteers to give him the old one-two, but he gets trapped in a cage in a moment of distraction. Coco goes through the same treatment, while Crunch is trapped on ice by a laser. As Cortex sets off with the captured prizes, Crash's good arm manages to throw Coco's machine at Aku Aku's cage, making it fall off somewhere in the woods.
After Crash frees Aku Aku, the two of them find themselves fighting strange mutant creatures of great proportions. Luckily for them, Crash can control these creatures with the help of Aku Aku's mystical powers, something that may just come in handy. The duo eventually arrives at the Mojo Temple, where they see Cortex's airship. Mojo is the essence of life itself, and this confirms Aku Aku's theory: Cortex and Uka Uka are stealing all the Mojo from the temple so they can make their mutants bigger, stronger and meaner. After our heroes make their way to the top of the temple, they find Cortex and Uka Uka, holding Coco as a hostage. Cortex reveals his evil plan to them: with the help of his mutated minions, he intends to build a giant robot - The Doominator - to crush Wumpa Island. Uka Uka sets off with Coco and the Mojo, while Cortex stays to watch one of his giant freaks destroy Crash. This doesn't go as planned, however, and Cortex is forced to flee when Crash gains the upper hand.
It's now up to Crash and Aku Aku to rescue Coco, fight Cortex's mutant army and stop The Doominator from being finished. But as they set off on their journey, Uka Uka shows great disappointment towards Cortex and announces his replacement...Nina Cortex. When Crash and Aku Aku made it to Cortex's lab, he had to fight Nina in a spiderbot called the Arachnina, try to jack her bot, and destroy the machines that powers The Doominator. Everything is peaceful again when Crash and Aku Aku stops Nina's plan.