Megamind (Will Ferrell) is a super-intelligent alien who has come from a different planet and landed in the Metro City (Metrocity) Prison. Megamind has constantly battled his nemesis Metro Man (Brad Pitt) since they both arrived on Earth as infants. Consistently losing to Metro Man in his schemes to take over Metro City, Megamind believes himself destined to be the villain. On the day that Metro City dedicates a museum to their protector, Megamind and his sidekick Minion (David Cross) kidnap reporter Roxanne Ritchie (Tina Fey), and then lure Metro Man into a copper-lined room. To everyone's surprise, Metro Man is unable to escape, and appears to be killed when Megamind's death ray strikes him. Megamind revels in his victory, but shortly after becomes depressed, his villainy having no meaning without anyone to stop him.



While attempting to destroy the museum, he disguises himself as its curator Bernard (Ben Stiller) to hide himself from Roxanne. As he talks with her, Megamind is inspired to create a superhero by injecting a worthy target with a serum fashioned from Metro Man's DNA, granting them Metro Man's super-abilities. As Megamind is selecting his target, Roxanne sneaks into Megamind's lair; in the resulting chaos, Megamind accidentally fires the serum into Hal, Roxanne's cameraman (Jonah Hill). Taking advantage of the gullible Hal, Megamind appears to the transformed human as his "space dad", grooming Hal into the superhero Titan (Hal's misunderstanding of Megamind's original name "Titan") and preparing him to fight Megamind in the coming days. Meanwhile, Megamind has become attracted to Roxanne, and continues to date her using his Bernard disguise. Titan, also infatuated with Roxanne, becomes jealous of Bernard, while Minion, seeing Megamind losing interest in villainy, angrily leaves him. On a dinner date, Megamind's disguise falters, leading Roxanne to dump him. Megamind, heartbroken, returns to his lair and vows to fight Tighten the next day as planned.



Megamind becomes impatient waiting for Titan and seeks him out, finding the superhero has used his powers for nefarious purposes. Megamind taunts Titan into fighting him by revealing his space dad and Bernard disguises. In the midst of the fight Megamind realises that Titan will not be satisfied with simply imprisoning Megamind after his loss, but intends to kill him. Megamind then tries to activate his safeguard scheme by capturing Titan in a copper-lined trap, and is shocked to find it fails to work. The villain flees, leaving the city to celebrate Titan's victory, until the "hero" reveals that he is taking over the city, and goes on a destructive rampage. Megamind returns to Roxanne, apologizing and convincing her to lead him to Metro Man's secret headquarters where they might find another way to stop Titan. They are surprised to find Metro Man still alive, secluded in his headquarters. Metro Man reveals he had become tired of fighting Megamind, and has changed into Music Man because he wanted to keep his logo, and had an epiphany that day, faking his own death to pursue his career as a musician. Without any new leads, Roxanne tries to convince Megamind to fight Titan as the city's hero, but Megamind feels he is destined to always be the villain, and turns himself back in to prison.



Later, Titan captures Roxanne and secures her to the top of Metro Tower, threatening to kill her if Megamind does not fight him. Seeing Roxanne in danger, Megamind pleads to the warden for his release, apologizing for all the wrongs he committed before. To the villain's surprise, Minion has disguised himself as the warden, accepts Megamind's apology, and the two take off to the city. They use an elaborate ruse, Minion disguising himself as Megamind to lure Titan from the tower, while Megamind disguises himself as Metro Man to save Roxanne and verbally berate Titan. Titan is temporarily bested, and told by "Metro Man" to leave "Metrocity" (Megamind's distinctive mispronunciation of "Metro City"), but the defeated hero soon returns, seeing through Megamind's disguise. Megamind is forced to run from Titan's wrath, until Roxanne discovers where Megamind left his invisible car and the tool to extract the superhero serum from Titan. Megamind successfully retrieves the device and uses it on Titan, reverting him to Hal. The city cheers for its new hero, a role that Megamind realizes he is capable of choosing himself.



In the aftermath, the former Metro Man museum is rededicated to Megamind, who became hero of Metrocity in a Metro Man disguise, who is slowly coming around to being the hero. He and Roxanne have developed a relationship, and hidden in the crowds, a concealed Music Man gives Megamind his congratulations.