Marvel Ultimate Alliance 2 continues the four-player mayhem of the previous Marvel Ultimate Alliance and, before that, the X-Men Legends series. It is based on the Secret War and Civil War storylines from the comics. After Nick Fury leads an unauthorized super-hero assault on Latveria and a fight gone wrong kills hundreds of civilians in Connecticut, the government passes the super-human registration act, which requires all super-powered individuals to reveal their identities to the government. At one point in the story, you have to choose the pro or anti registration side and certain heroes will always be on one side or another, locking them out if you choose the other path. The game after this point changes depending on the storyline you choose.

You start with a handful of characters and can unlock more by completing bonus simulator missions, which will give you a special task like blowing up cars. There are four heroes active at all times during the game, unless they get knocked out. Each character has a health meter and a stamina meter. You can use SHIELD access points, usually at the beginning and middle of each level, to switch out characters. The stamina meter recharges on its own and controls use of powers. Each hero has a jump (which can also be used to double-jump, fly or web-swing, depending on the character), grab, quick strike and powerful strike. These can be used in combination to do things like jumping attacks, pick up an enemy, then punch them, etc. Combining these with a modifier button allows you to use powers. Each hero has a wide variety of powers. Leveling up gives you points to spend on improving the powers. You can re-assign the points and change which powers are active at any time.

Defeating enemies and smashing environment items gives you health refills and points that can be spent upgrading statistics for each hero. There are also items that you can carry that will give stat bonuses like increased HP or a bonus to a specific type of damage.

The big change over the previous game is the addition of fusions, which are two-character team-up attacks. This is controlled by a meter of four stars. You fill this by defeating enemies or finding an item that instantly fills the whole meter. You can spend one star to revive a fallen teammate or all four to perform a fusion attack. Any possible combination of two characters has their own unique fusion. There are three basic types:

There are targeted fusions, like having Things throw Mr. Fantastic at someone. These do high damage to a single target and are good for using on bosses. There are also clearing fusions, like having Storm bounce her lighting off Wolverine. These damage all enemies in a given radius. Clearing fusions are good for clearing out a clump of enemies. Finally, there are guided fusions, like Iceman and Human Torch shooting their powers at each other, then running around mowing down anyone who gets between them. These are good for clearing out scattered enemies.