Soul Eater: Medusa no Inbō is an action game based on Square Enix's manga and anime series Soul Eater. Shibusen is a special school where people learn to become Shinigami. To do so, they must absort 99 demon souls and the soul of a witch for the weapon to finally become a Death Scythe. Training is also part of Shibusen student's schoolwork. The player controls one of three protagonist teams consisting of a Meister, the weapon wielder, and a Weapon, a human capable of shape-shifting into a weapon: Maka and Soul, a Scythe, Black Star and Tsubaki, a Katana (she can also change into a variety of ninja tools), and Death the Kid and the gun sisters Liz and Patty.

The player moves the characters around using the directional buttons, and attacks using the stylus. The Meisters and Weapons play differently and the player can switch between the two to make use of each one's abilities. For instance, Maka uses melee attacks while her partner, Soul, uses ranged attacks. Doing the trainings assigned to the student will reward them with experience and ability points.