The Simpsons Bart vs The Space Mutants is a platform game where the player takes on the role of Bart Simpson and must stop the Space Mutants from invading Springfield. On each of the five levels, Bart must collect or get rid of the ingredients that the Space Mutants are planning to use to build their machine, such as purple objects or balloons. He also needs to collect enough "proof" of the aliens' existence (brown coins left behind when they are jumped on), so his family members will help him when he meets a boss (characters such as Nelson and Sideshow Bob). This won't be easy since the Space Mutants are using human bodies as disguise.
The gameplay involves Bart using his X-ray Specs to figure out who the real Space Mutants are. The ways Bart can get rid of those objects sought by the Space Mutants are numerous. For instance, in the first stage, Bart must get rid of purple objects. He can dye them red, cover them, wash them, etc. Some even involve a little puzzle solving, like playing a trick on Moe to make him get out of the bar. Bart also has some coins that can be used in many ways throughout the game, like buying things, getting devices operating, etc. Those coins are essential to solve some puzzles in the game.