Megamind is a super intelligent alien who was evacuated from his homeworld as a baby, as was Metro Man; the two fall into paths of super villainy and superheroism respectively and grow up as rivals fighting for control of Metro City. Megamind is consistently defeated by Metroman and is in prison. After using a holographic watch to escape with the aid of Minion, a talking fish with the robotic body of a gorilla, he kidnaps Metro Man’s supposed love interest, reporter Roxanne Ritchi and holds her hostage to lure him into a trap. Finding that copper is Metro Man’s one weakness, Megamind’s plan to obliterate him with a death ray powered by the sun succeeds, and Megamind finally takes over the city. His joy is short lived though, as without a hero to fight, he finds his life has become meaningless. He goes to the Metroman Museum, which was dedicated to him on the day of his death and nearly runs into Roxanne. He uses his holographic watch to disguise himself as the museum’s curator Bernard, and she innocently gives him the idea of creating a new superhero to take Metro Man’s place. After creating a formula from Metroman’s DNA, Roxanne intervenes in his plans and he accidentally injects the serum into Hal Stewart, Roxanne’s dimwitted cameraman, who has an unrequited crush on her. Under the guise of his “Space Dad”, Megamind tries to mold Hal into a superhero named Titan (misheard by Hal as “Tighten”), as it was the only name he could trademark. Unfortunately, Hal’s ambitions are crushed when he sees Roxanne and Megamind as Bernard on a date. However, Megamind’s disguise falters during dinner and she rejects him, causing him to lose track of his invisible car which contains the gun capable of removing Hal’s powers.
On the day of their planned battle, Hal doesn’t show up and Megamind finds that he has been using his powers for ill-gotten gains and wants to team up with Megamind to take over Metro City. Megamind tells Hal that he tricked him, revealing his Space Dad and Bernard disguises, but that infuriates Hal, who tries to destroy Megamind. Megamind activates a failsafe to trap Hal in copper as it was Metro Man’s weakness, but that too fails. After he escapes, Megamind pleads with Roxanne for help, and they go to Metro Man’s hideout to search for clues to why the copper didn’t work. Instead they find Metro Man, still alive but having been disillusioned with the life of a superhero, he chose to fake his death in order to pursue a career in music. He refuses to help despite the danger, but encourages Megamind that good will always rise up against evil. Not seeing himself as a hero, Megamind gives up and returns to prison. Meanwhile, Hal kidnaps Roxanne and holds her hostage to call Megamind out of hiding. Megamind begs the Warden to release him to face this threat, inadvertently apologizing for an argument he’d had with Minion earlier that caused the two to separate. Minion reveals himself under the Warden’s disguise and the two leave to face Hal together.
At Metro Tower, Hal threatens to send it toppling into the city with Roxanne tied to the roof. Megamind appears and tricks Hal, freeing Roxanne and the two flee as he throws the tower at them. Roxanne gets away, but Megamind is struck by the tower’s antenna and appears near death. Metro Man finally appears and chases Hal away from the scene as Roxanne discovers that the Megamind that saved her was actually Minion, and that Metro Man is actually Megamind in disguise. He successfully scares Hal off, but accidentally mispronounces the city’s name as Metrocity, as Megamind often did and Hal returns. Finding the invisible car, Megamind grabs the diffuser gun just as Hal hurls him into the sky. To avoid falling to his death, Megamind dehydrates himself and lands with the gun in the fountain in front of Hal, re-hydrating and then hitting him with the gun, removing the villain’s powers and returning him to normal. Now hailed as heroes, Megamind and Minion appear at the reopening of Metro Man’s museum, now dedicated to Megamind instead while Metro Man, in disguise within the crowd silently congratulates his former rival.
In a mid-credits scene Minion is doing the laundry when a re-hydrated Bernard pops out of the washing machine. After chiding Megamind about cleaning out his pockets, he knocks Bernard out with the Forget-Me Stick.