In the city of Mitakihara, a 14-year old girl named Madoka Kaname and her best friend Sayaka Miki are approached by a strange familiar named Kyubey. This creature offers a contract in which a girl can have any wish granted in exchange for becoming a magical girl tasked with fighting against Witches, manifestations of despair that are responsible for unexplained murders and suicides. Meanwhile, a transfer student named Homura Akemi tries to stop Madoka from becoming a magical girl at all costs. As Madoka contemplates becoming a magical girl, she learns that a magical girl's life isn't as glamorous as she thought and is filled with anguish, suffering and despair. Soon coming to learn the dark secrets between magical girls and witches and the burden it places on her friends, Madoka struggles to decide if there really is a wish worth risking her life for.

The spin-off manga, Puella Magi Kazumi Magica: The Innocent Malice, takes place in Asunaru City and follows an amnesiac magical girl named Kazumi who, along with a band of other magical girls known as the Pleiades Saints, starts to discover the dark nature of magical girls as she regains her memories. Puella Magi Oriko Magica takes place in an alternate timeline to the main series, in which Homura, Mami Tomoe and Kyōko Sakura, along with a young orphaned girl named Yuma Chitose who was abused as a child by her mother, find themselves up against a magical girl pair, Oriko Mikuni and Kirika Kure, who are hunting other magical girls.[3] The prequel story, Puella Magi Oriko Magica: Noisy Citrine, follows Kirka as she starts out being a magical girl and has an encounter with her old childhood friend, Erika. Puella Magi Madoka Magica: The Different Story also takes place in an alternate timeline, mainly focusing on Mami's relationships with the other magical girls.