Starring Keith Ferguson, Laura Post, and Josh Brener, the film follows Megamind, now a superhero, as he protects Metro City from his former allies in the Doom Syndicate, a team of supervillains.

Keeping his old crew fooled, Megamind reveals an abandoned villainous plot he conducted of launching Metro City to the Moon using rockets planted underground.

Realizing that he cannot defeat the Syndicate alone, Megamind tracks Chum inside his remodeled diner and attempts to enlist his help.

Megamind, Chum, Roxanne, and Keiko team up to face the Doom Syndicate, but fail to stop the launch.

Roxanne is elected the new Mayor of Metro City, while Keiko launches a hero signal as Megamind feels accomplished in his new team.

In a mid-credits scene, the Doom Syndicate are locked back up in prison, where they are visited by Megamind's former mentor, Machiavillain.

"[1] In February 2022, it was announced that Peacock had ordered DreamWorks Animation Television to produce a spin-off series titled Megamind’s Guide to Defending Your City.

[3] In February 2024, DreamWorks Animation Television revealed a trailer for Megamind vs. the Doom Syndicate, with Keith Ferguson, Laura Post, Josh Brener, Maya Aoki Tuttle, Emily Tunon, Talon Warburton, Scott Adsit, Chris Sullivan, Tony Hale, Jeanine Mason and Adam Lambert as part of the main cast.

[9] In a two out of four-star rating for RogerEbert.com, Nell Minow states the film "is intermittently funny and briefly heartwarming, as though they ran the original through the washing machine a few times, and then faxed it.

"[10] Ryan Leston of IGN called the film "a lazy, 14-years-too-late cash-in on DreamWorks IP", giving a four out of ten rating, adding that it "sets up a riotous romp through superhero cliché, but simply fails to deliver".