Teenage Mutant Ninja Turtles: Smash-Up is a versus fighting game released in conjunction with the 25th anniversary of the Ninja Turtles franchise. Created by Game Arts, co-developer of Super Smash Bros. Brawl, Smash-Up has many similarities with that title, with similar game modes, gameplay and controls. The game takes inspiration from various versions of the Turtles throughout the years: the character models are based closely on those from the 2007 animated film, while the character voices are provided by the cast from the 2003 series. Story sequences are shown in monochrome comic artwork drawn by veteran Turtles comic artist Jim Lawson with the story provided by franchise co-creator Peter Laird.

Single player game modes include:

• Arcade: the main single player story mode. Selecting from the four turtles, Master Splinter, April O'Neil or Casey Jones, players fight through eight battles, with several mini-games in between. Each character has their own ending sequence.
• Practice: practice against a single enemy who can be set to pursue various strategies or be idle.
• Mission: a series of 51 consecutive missions, each with a set goal. These include only using or finishing with certain moves or protecting a certain character from harm.

Modes playable with multiple players (with customizable rules, playable off- or online) include:

• Battle Royal: free-for-all match.
• Tournament: for up to eight players.
• Swap Out: the winner of a match stays on for the next fight.

Finally, Survival mode tasks players with fights against an endless number of enemies.

Fighting moves include weak and strong attacks, special ninja powers, grabs and throws, guards, jumps and double jumps. Matches are won by depleting the enemy's health or throwing them out of the arena. Power-ups appear randomly during a fight, including one-time use weapons or pizza for health replenishment.

Besides the seven starting characters, the game includes a further five that can be unlocked by beating the arcade mode. Exclusive to the Wii version are a further four characters, including several variations of Rabbid from Ubisoft's Raving Rabbids series. Besides several unlockable levels, other hidden bonuses are alternate costumes for all characters and comic covers, concept art, and trailers from various Turtles incarnations.