Two infant aliens are launched into Metro City on Earth when their planets are sucked into a black hole. One of them is raised by a wealthy family while the other is raised in a prison. A rivalry starts between the two and while the former becomes the superhero Metro Man, the latter becomes the evil super-villain Megamind.
Megamind and his henchman Minion abduct reporter Roxanne Ritchi on the day of a celebration for Metro Man and hold her hostage at a fake observatory. Metro Man breaks into the real observatory to rescue her, but is trapped inside. Metro Man suddenly starts to become weakened and explains that his weakness is copper, which the observatory is made out of. Megamind fires a sun-fueled ray at the observatory, obliterating it, and Metro Man apparently dies in the blast. With nobody to oppose him, Megamind assumes control over Metro City.
However, Megamind soon finds himself without meaning with Metro Man gone. Megamind holographically disguises himself as the Metro Man museum curator Bernard, locking the real Bernard in a dehydration cube with his gun. Roxanne unintentionally gives the disguised Megamind the idea to use Metro Man's DNA to inject it into someone else and give them Metro Man's superpowers. However, Roxanne and her cameraman Hal Stewart appear and try to stop Megamind. In the process, Hal is injected with the serum, giving him super-powers. Megamind disguises himself as Hal's space-dad and trains him to become Metro City's protector while spending time with Roxanne as Bernard, unaware that Hal has feelings for Roxanne as well.
Hal professes his love for Roxanne, but is rejected. Hal later witnesses Roxanne on a date with the disguised Megamind, but after he leaves, Roxanne accidentally shuts off the holographic disguise, exposing Megamind. Roxanne angrily rejects him, and a bitter Megamind misplaces his invisible car holding the anti-serum to revert Hal to normal. Megamind, renouncing himself as the bad guy, shows up in the city the next day to fight Hal, armed in a giant robotic suit, but Hal refuses to appear. Megamind confronts Hal in his apartment and reveals his deception, enraging Hal. The two battle each other throughout the city, culminating in Hal destroying the robot. However, Hal reveals that he intends to kill Megamind in retribution, forcing him to flee. However, Hal goes on a rampage throughout the city in his rage.
Roxanne leads Megamind to Metro Man's hideout, which turns out to be the school they originally went to. There, they discover Metro Man, who had faked his death to become a musician instead of a super-hero. Metro Man refuses to fight Hal, so Roxanne attempts to convince Megamind to stop him, but Megamind refuses and turns himself over to prison. Roxanne tries to reason with the enraged Hal, but is taken hostage on top of the Metro Tower where Roxanne first rejected him. Megamind, seeing Roxanne in danger, pleads to the warden to be set free so he can fight Tighten. The warden is then revealed to be Minion in disguise, who frees Megamind.
Minion, disguised as Megamind, rescues Roxanne from Metro Tower, but Tighten spears him through the chest with the pinnacle of Metro Tower. Before Tighten can kill Roxanne, Megamind arrives, disguised as Metro Man. Tighten flees in terror, but returns upon recognizing the way Megamind pronounced Metro City. The two battle, during which Megamind manages to locate the invisible car holding the anti-serum. However, Megamind is flung into the air by Tighten before he can inject him with it. Tighten corners Roxanne in a fountain, but Megamind, who had shot himself with the dehydration gun in midair, plummets into the fountain and rehydrates in front of Tighten before successfully injecting him with the anti-serum. Tighten is stripped of his powers and incapacitated as a result. Megamind shortly afterwards revives Minion by tossing him in the fountain.
Hal is incarcerated while Megamind is hailed a hero and becomes Metro City's new defender, with Roxanne becoming his fiancé. As the city celebrates, a disguised Metro Man secretly attends and congratulates Megamind for his heroics.
- Will Ferrell as Megamind.
- Brad Pitt as Metro Man.
- Tina Fey as Roxanne Ritchi.
- Jonah Hill as Hal Stewart.
- David Cross as Minion.
- Ben Stiller as Bernard.
- Justin Theroux as Megamind's Father.
- Jessia Schulte as Megamind's Mother.
- Tom McGrath as Lord Scott/Prison Guard.
- Emily Nordwind as Lady Scott.
- J.K. Simmons as Warden.