Picking up right after the events of the movie, DreamWorks Megamind: Ultimate Showdown allows players to take up the role of Megamind in order to take on the villains of the Doom Syndicate. Megamind alternates between four weapons - a De-Stroy gun (pew pew pew), De-Hydrate gun (will shrink objects and enemies), Blower Glove (watch your enemies scramble to remain upright as you blast them with your portable tornado) and a Tesla Glove (creates electrical discharges of shocking strength).

The game is comprised of about nine mission levels, with access to Megamind's Lair as a Hub in between missions. The player must collect glowing tokens known as B.I.N.K.E.Y in order to upgrade Megamind's weapons. B.I.N.K.E.Y is collected by defeating the Doom Syndicate enemies, or destroying objects within the game.

There are also mini-games unlocked throughout that can also be accessed from within Megamind's Lair. The mini games include a Pod Racer, which is a simple timed race. The Sticky Boots game, which requires Megamind to climb up the side of a skyscraper using his magnetic boots whilst avoiding obstacles thrown out of windows above. The Rampage game, a callback to the classic arcade game Rampage. You are given Megamind's Battle Suit to destroy as much of the city as possible in a given time limit. The Mega-Blast game, another rampage style game but this time with a first person view from within Megamind's Battle Suit. Finally the Mega-Ball game, where you will find Megamind locked inside a ball much like an 80's plasma globe. The goal is to control it and make your way through an industrial themed track before the timer runs out. No easy task, given the difficulty of maneuvering within what is essentially a hamster ball. The track will give the player the novelty feeling of being inside a ping pong machine, with lots of twists and turns, moving environmental items such as running across the trailers of moving trucks, and pipes to fall into that shoot the player out into a new area.

Two-player co-op mode is included, although the second player doesn't have as much control as Megamind's character. It was designed to give a guardian or parent the opportunity to help their child, or a younger sibling, without the possibility of impeding player one's progression. Player two will control a brainbot with the ability to move around the level and shoot. All puzzles and tutorials are aided by Minion (the fish in the gorilla suit) who will chime in over the intercom whenever the player becomes obviously stuck with some helpful hints.