This game carries on the story as to what happens after the Megamind movie's events. Up to four players can play as Megamind and any of 8 other characters as they combat a crime wave by The Doom Syndicate and their goons. Make your way through story mode and once each chapter is beaten it unlocks battle modes that can be played at any time.

The action involves mostly beat 'em up areas with occasional shooting sections where buildings are partially destructible. Use the Wii Remote and Nunchuk to jump, throw objects, melee attack or long-range shoot the villains. Collect power-ups for health, shields, and damage boosts, Build inventions such as a Mega Essence Tracker and Bio Essence Neutralizer to track and defeat the villains.