Dr. Neo Cortex is both Crash's creator and arch-nemesis. He is a genius scientist stubbornly bent on world domination and evil plans. He is well known for kidnapping animals from the jungle and mutating them with a contraption called the Evolvo-Ray. Crash Bandicoot was originally intended to be the general in his army of super animals, but the experiment failed when he couldn't control Crash's mind. Crash has since been Cortex's sworn enemy and he always shows up to put an end to whatever diabolical scheme the big-headed doctor may have in mind.

The doctor's only shred of affection goes towards his beloved niece, Nina Cortex. As an evil scientist, Cortex was disturbed by Nina's kind nature, and that ultimately made him send her to the Academy of Evil. He also replaced her hands with bionic versions, making her much stronger, and, at the same time, keeping the fragile and innocent animals she once adored away from her.

Cortex would do anything to conquer the planet and rule it as he saw fit, and his ego is just as large as his head. His maniacal speeches are sometimes accompanied with oddly poetical metaphors, but this is hard to notice because he's so uptight and anti-social. He makes up for what he lacks in physical power with intelligence, manipulation and a trustworthy ray gun. Despite his intellect, Cortex is quick to throw a tantrum when things don't go his way.

There is a certain rivalry between Cortex and Nitrus Brio, the scientist who perfected the Evolvo-Ray and came up with the genetic techniques he uses (Cortex even took credit for this early on, which led Brio to turn against him). N. Gin is the only other scientist who remains loyal to him, though he acts more like a servant than a proper partner. Though Cortex is the mastermind in the opposition against Crash, he is actually somewhat of a lackey to Uka Uka, the evil witch doctor spirit who always gets furious at Cortex's failed attempts for World domination.