Megamind and Metro Man are life-long rivals in Metro City. Both are alien orphans sent to Earth from their dying planets but raised in far different circumstances, with Metro Man becoming a superhero defending the city from Megamind’s villainous plans that he executes with help of his henchman Minion, a fish-like creature in a mechanical suit.
Megamind kidnaps Metro Man’s girlfriend and reporter Roxanne Ritchi and lures the hero to a copper-lined observatory. Metro Man collapses and reveals copper to be his weakness, allowing Megamind to kill him with a death ray. Megamind quickly takes over the city, but finds that with no one to challenge him his life has no meaning.
Megamind prepares to destroy the recently opened Metro Man museum, but when he sees Roxanne wandering inside, he takes on the holographic disguise of Bernard, the museum curator (temporarily dehydrating the real Bernard into a small cube). Megamind finds himself attracted to Roxanne, and from her, gets the idea of creating a new hero to fight. In his lab he creates a serum from Metro Man’s DNA to give his target superhero powers, but it is accidentally injected via his defuser gun into Hal Stewart, Roxanne’s dimwitted cameraman when she enters the lab. Megamind finds Hal is easily coerced, and using a hologram of “Space Dad”, trains him to become a superhero. Hal takes the name “Tighten”, misunderstanding Megamind’s suggested “Titan”. Meanwhile, Megamind continues to see Roxanne using the Bernard disguise.
Feeling Hal is ready, Megamind schedules a date for the two to fight. However, on the night before Megamind has a falling out with Minion, while Hal sees that Roxanne has no feelings of him as she prepares for a date with Bernard, and he goes on a crime spree. While on her date with Bernard, Megamind’s disguise falters, and she leaves him, causing Megamind to also misplace his invisible car and the defuser gun.
Megamind tries to get Hal to fight him by revealing all of his disguises and manipulations and infuriating Hal further. Fighting now for his life, Megamind traps Hal in a ball of copper, but it fails to do anything. Confused, he finds Roxanne and asks her to take her to Metro Man’s secret lair to find out any other weaknesses. There, both are surprised to find Metro Man alive; he feigned his death as he wanted to retire and take up country music. He refuses to help, but reminds Megamind a hero will always emerge to challenge evil.
Feeling responsible, Megamind turns himself into the authorities and is imprisoned, while Roxanne tries to appeal to Hal directly, but instead ends up captured. Hal challenges Megamind to a fight, threatening Roxanne. Megamind appeals to the warden to let him free, and surprised to see that the warden was Minion in disguise.
Megamind and Minion uses holographic disguises to trick Hal into believing that Metro Man is back, but Hal sees through it based on Megamind’s odd pronunciation patterns. Hal attacks Megamind, and during the fight, he finds his invisible car. He recovers the defuser gun and shoots Hal with it, reverting him to human form.
Hal is arrested for his crimes, while Megamind is treated as a hero by the city and Roxanne. In disguise in the crowds, Metro Man congratulates his former foe.
In a mid-credits scene, the original Bernard is rehydrated while Minion is doing the laundry, and Minion knocks him out before he asks too many questions.