While playing with his Game Boy Advance, Wario becomes frustrated with his game to the point of smashing it. He requests Dr. Crygor's help in mending it. Crygor, however, places it in his washing machine, which spits out dozens of buttonless objects similar in form factor to a Game Boy Advance. It transpires that in order to play, the device must be physically moved. Mona and 9-Volt arrive and toy with these new units, enjoying themselves. Wario, taking note of their reaction, decides to take advantage of these motion-sensing abilities as a selling point, and recruits his friends to design Microgames based on this concept.

This game changes the scoring from the other WarioWare titles. Previously, the score was the number of games that were played, but Twisted! only counts the number of games that the player won. The game features items called "souvenirs", which are unlocked after boss stages in story mode. Records, musical instruments, figurines, games, and many quirky items are possible to unlock.