After Megamind causes an accident that makes Mr. Donut lose his memory, he convinces himself that the loveable shop owner is on the verge of turning evil and vows to stop him before he becomes a supervillain.

When Chum accidentally sprays a roach with an experimental intelligence substance that causes it to become a super genius, Megamind, Keiko and Chum must get rid of the spray and contain the roaches before they take over the city.

When Megamind's body-switching tech causes him and Roxanne to swap bodies, they must figure out how to act as the other before unleashing too much chaos and destruction on the city.

Roxanne's rekindled friendship with an old camp buddy makes Megamind jealous, so he reprograms Keiko's robot science project to act as his new best friend.

Chum clones himself to get everything accomplished and take care of an ill Megamind; when the clone makes additional copies of himself, things get out of hand.

Megamind refuses to teach Keiko how to be a hero, so she takes it upon herself to go undercover in the Doom Syndicate to prove herself.

Megamind's confidence is tested when Machiavillain finally reveals himself to the blue hero and puts him through a series of challenges to save the city from destruction.