In the world of spoof superheroes, Megamind (voiced by Will Ferrell), the greatest villain in the world, is locked in an eternal battle against the seemingly invincible and perfect Metro Man (Brad Pitt). However, in their last confrontation over go-to Damsel in Distress Roxanne Ritchi (Tina Fey), Megamind finally (and surprisingly) manages to defeat his Arch-Nemesis.
After initially gloating over his victory, Megamind soon realizes that his greatest wish is not all it's been cracked up to be. With the help of his loyal Minion (David Cross), Megamind decides to create a new hero to make his status meaningful. He chooses Roxanne's awkward camera man Hal Stewart (Jonah Hill) and trains him to become a new hero called "Tighten". Unfortunately, Tighten, instead of using his powers for good, sets out for mass destruction, positioning Megamind to save the day for the first time in his life.