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.

With Metro City once again thinking that Megamind is a villain, he must make his way through town without being spotted. Things become complicated when a plucky 7-year-old boy thinks he's the hero who can stop Megamind.

Megamind swaps powers with Metro Man while fighting a new villain known as Destruction Worker.

After Machiavillain mind-controls the citizens of Metro City, it's up to Megamind and Keiko to find a way to cure them all.