In Teenage Mutant Ninja Turtles: Manhattan Missions, players control one of the four turtles, each equipped with unique weapons and abilities, to combat crime across New York City. The game features a side-scrolling mechanic where players can level up their turtles' stats, such as strength and speed, through combat.

The storyline of Teenage Mutant Ninja Turtles: Manhattan Missions revolves around the turtles racing against time to thwart Shredder's plan to take over New York City within 48 hours, while also addressing various crimes that lead back to him.

Teenage Mutant Ninja Turtles: Manhattan Missions stands out with its real-time 48-hour gameplay mechanic, requiring players to manage their turtles' health and strategize their missions, alongside the exploration of diverse environments and the need to solve puzzles to progress.