Megamix features a Story Mode in which players try to help a character named Tibby reach Heaven World, his home. Playing through Rhythm Games earns Medals that can be used to unlock bonuses such as additional rhythm games. Each Rhythm Game also features a special Skill Star point, which awards bonuses for hitting a certain part of the game with precise timing. Ratings for the Rhythm Games are now awarded based on a score meter indicating how well the player performed. Tower-themed elements are incorporated into the remix while every character in the present rhythm games get to wear special tower-themed alternate costumes (except for the Left-Hand, Right-Hand and Final Remixes).

The game features over 100 Rhythm Games, including 70 taken from previous titles (including the GBA release, which was never released outside of Japan) and 30 brand new ones, as well as new Remix stages based on the game's Rainbow Towers which combine the previous rhythm games in the tower (or more rhythm games) into one song. The game can be optionally played with the stylus, though controls are more simplified compared to Rhythm Heaven.

The game uses the traditional control scheme featured in the original Rhythm Tengoku, which uses the A, B, and directional buttons on the Nintendo 3DS. Like the previous three entries in the series, Rhythm Heaven Megamix is composed of several Rhythm Games, requiring players to play in time with the music in order to clear each one. See also: Gameplay of the Rhythm Heaven series

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