The Teenage Mutant Ninja Turtles III Radical Rescue takes place one year after the events of the last game. Shredder has escaped from prison and managed to capture turtle-friendly reporter April O'Neal once again! This time, he captures three of the turtles - Raphael, Donatello, and Leonardo - before the game even starts. The player takes on the role of Michaelangelo as he sets out on a quest to rescue his pals and restore justice to the city.
The gameplay in Teenage Mutant Ninja Turtles III Radical Rescue differs from previous Ninja Turtle games with its level structure. Instead of linear levels, the game features one huge interconnected fortress. Progress is made by finding bosses hidden within the fortress, defeating them, and using the keys they leave behind to open up new rooms. When a captured turtle is found, they become a playable character.