When a planet is about to be destroyed, two alien offspring are saved by their parents that launch them into space in pods. Their fate on Earth is opposite: one who is a beautiful baby with superpowers crashes in the lawn of a mansion, while the other who is ugly and blue with a big head crashes in a prison yard with his companion Minion. They are raised in different environments of Metro City but study in the same school for gifted children. While one becomes popular but selfish, the other is absolutely outcast by the other students.

They become enemies and when they grow up, the population knows them as the superhero Metro Man and the villain Megamind. In their fights, Megamind always loses and ends up in prison; however, Megamind develops a ray that kills Metro Man, reducing him to a skeleton. After a short period, Megamind feels bored without the battles against Metro Man. Meanwhile he dates field reporter Roxanne Ritchie, who works with cameraman Hal Stewart, using the identity of curator Bernard and sooner they fall in love with each other.

When Megamind decides to create another superhero to become his opponent, he accidentally transforms Hal Stewart into the super-powered Titan, expecting that he would use his powers for good. However, Titan becomes greedy and evil and destroys Metro City. Now Megamind is the only hope to save the world from the mean Titan.