Ninth-grader Mami Tomoe is not your average middle schooler. While she regularly attends Mitakihara Middle School, she also works as a magical girl—one who has made a wish in exchange for magical powers and a new duty to seek out and destroy otherworldly beings known as witches. But Mami is also a special case among magical girls—while most fight for their own sake, Mami prefers to work with others, becoming a guardian of justice who destroys any evil creatures she can find, whether it be a witch or a mere familiar. It is this selfless lack of self-interest that often distances her from other magical girls, and as a result, Mami is often lonely.

During one of her usual witch hunts, she finds a novice magical girl struggling against a particularly strong witch. After Mami lends her help, the magical girl introduces herself as Kyouko Sakura from the city of Kazamino. Impressed by Mami's skill and hospitality, Kyouko quickly requests to team up with her and become her apprentice.

Beginning as an adaptation of one of the hit anime's drama CDs, Mahou Shoujo Madoka★Magica: The Different Story is a tale of the relationship between two magical girls shown from an alternate perspective.