Metamor Panic: Doki Doki Yōma Busters!! is a visual novel-style adventure game with RPG elements. The adventure scenes mostly proceed linearly, with the player occasionally asked to choose an action, such as choosing what subject to ask a character about, or investigating a certain object. Combat sequences will also occasionally occur, which take a standard turn-based JRPG format where the three characters fight against yōkai. The game doesn't simply use the trappings of an RPG for flavor; it includes leveling up, character stats, and item management and, unlike many games in this style, there is the possibility of losing fights leading to a game over.

One day, high school student Masaki is camping in the woods with his friends Ai and Yuki. While exploring, they stumble upon a strange cave, and wind up releasing the seal on an ancient demon lord. The demon lord curses Ai and Yuki, causing them to transform into animals, and escapes to wreak havoc and release yōkai into the city. With the help of the demon hunter Genji, Masaki and his friends must stop the demon lord and lift the curse on the girls.