"Yamada-kun to 7-nin no Majo" centers on Ryu Yamada, a delinquent high school student known for his rebellious behavior and poor academic performance. Despite his tough exterior, Yamada feels unfulfilled and disconnected from his school life. His routine changes dramatically when he accidentally kisses Urara Shiraishi, the school's top honor student, during a fall. This unexpected event triggers a body-swapping phenomenon, allowing Yamada and Shiraishi to switch bodies. Intrigued by this strange occurrence, they investigate further and discover that the cause lies in the existence of witches within their school.

The series introduces a group of seven witches, each possessing unique supernatural abilities tied to specific conditions. Yamada and Shiraishi, along with their friends, form the Supernatural Studies Club to uncover the identities of these witches and understand the nature of their powers. As they delve deeper, they learn that the witches' abilities are linked to a mysterious phenomenon involving the school's history and a hidden magical artifact. The club members work together to resolve conflicts arising from the witches' powers, which often lead to unintended consequences and emotional turmoil.

Key characters include Ryu Yamada, whose initial apathy transforms into a sense of responsibility as he becomes more involved in the club's activities. Urara Shiraishi, despite her academic perfection, struggles with social interactions and finds solace in her growing bond with Yamada. Other members of the Supernatural Studies Club, such as Toranosuke Miyamura, Nene Odagiri, and Noa Takigawa, contribute their unique personalities and skills to the group's efforts. Each witch they encounter has a distinct ability, ranging from mind-reading to time manipulation, and their stories often intertwine with the club's mission.

The narrative explores themes of identity, relationships, and the consequences of wielding power. As Yamada and his friends navigate the challenges posed by the witches' abilities, they uncover deeper truths about themselves and the world around them. The series balances humor, drama, and supernatural elements, creating a dynamic and engaging storyline. By the end, the characters' journeys lead to resolutions that address the mysteries of the witches and the impact of their powers on the school and its students.