Megamind has taken on the role of Metro City’s defender, along with Ol’ Chum (formerly Minion), and they successfully thwart the Go-Fish gang from stealing a valuable fish. In recognition of his heroism, Megamind is given the key to the city. However, Chum feels underappreciated and expresses his desire to be Megamind’s sidekick. When Megamind rejects the idea, Chum decides to seek other opportunities, which Megamind reluctantly allows.

The Doom Syndicate, a group of supervillains and Megamind’s former allies, break out of prison and visit him, mistakenly believing his heroism is part of an elaborate evil scheme. They go on a crime spree and challenge Megamind to prove his villainous credentials by robbing a bank. Megamind struggles but is assisted by Keiko Morita, his biggest fan, who helps him stage a fake robbery. Meanwhile, Chum finds work at a dilapidated diner.

Megamind keeps up the ruse with the Doom Syndicate, revealing an old villainous plan to launch Metro City to the Moon using underground rockets. The Syndicate prepares to activate the rockets, but Megamind delays them. They grow suspicious and vow to launch the city themselves or destroy it. Realizing he needs help, Megamind tracks down Chum at his diner and tries to recruit him, but he begins to regret pushing Chum away.

The Doom Syndicate discovers Megamind’s deception and overpowers him. Feeling defeated, Megamind hides in an alley, where he is found by Roxanne and Keiko. They remind him that it is okay to ask for help. Chum also returns, and Megamind acknowledges him as his true sidekick. Together with Roxanne and Keiko, they form a team to confront the Doom Syndicate.

Despite their efforts, they fail to stop the rockets from launching Metro City. However, they manage to redirect the city back to Earth. Roxanne is elected the new Mayor of Metro City, and Keiko creates a new hero signal. Megamind feels a sense of accomplishment with his new team.

In a mid-credits scene, the Doom Syndicate is shown back in prison, where they are visited by Megamind’s former mentor, Machiavillain, hinting at future conflicts.