In his evil plot to take over the Mushroom Kingdom, Fawful tricks Bowser into eating a magic mushroom. The mushroom causes Bowser to begin inhaling everything around him, including Mario, Luigi and Princess Peach! Do the Mario Bros. have the guts to rescue Peach and escape
- Players are in control of two separate storylines. One features Bowser and his efforts to stop an arch-villain from taking over his castle. Meanwhile, inside Bowser, the microbe-sized Mario & Luigi must muscle their way through challenges and keep their nerve if they want to find a way out. They take action to control Bowser from the inside but without his knowledge.
- Players can switch between storylines at will. What happens inside Bowser affects what hes doing on the outside. Sometimes Mario & Luigi must solve puzzles and challenges behind the scenes to help Bowser overcome various obstacles and advance the plot.
- Players must make well-timed button presses to enhance their performance during battles and challenges. In some battles, Bowser grows so large that players must turn their Nintendo DS or Nintendo DSi system sideways, blow into the microphone or tap on the touch screen with the stylus to keep up with the action.
- The game features the same hilarious dialogue that has been the hallmark of the Mario & Luigi series.