"Murenase! Seton Gakuen" is a comedic and educational manga series set in Seton Academy, a school where human students coexist with anthropomorphic animals. The story centers on Jin Mazama, a human boy who harbors a strong dislike for animals due to a childhood trauma. Despite his aversion, Jin finds himself surrounded by animal students, including Ranka Ookami, a wolf girl who becomes infatuated with him after he saves her from starvation. Ranka’s persistent attempts to join Jin’s "pack" create much of the series’ humor and conflict.

The narrative explores the dynamics between humans and animals in this unique school environment, often blending slapstick comedy with factual information about animal behavior and biology. Jin’s reluctance to engage with the animal students gradually softens as he forms bonds with them, particularly with Ranka and other members of their growing group. The group includes characters like Hitomi Hino, a human girl who is overly enthusiastic about animals, and Miyubi Shishiro, a shy and reserved lion girl. Each character embodies traits of their respective species, which are frequently highlighted for comedic effect and to provide educational insights.

As the story progresses, the group navigates various school activities, interspecies relationships, and challenges that arise from their differences. The series often uses these situations to explore themes of coexistence, understanding, and the importance of community. While the tone is predominantly lighthearted, it occasionally delves into more serious topics, such as the struggles of endangered species and the complexities of animal instincts conflicting with human-like emotions.

The manga balances its comedic elements with a focus on character development, particularly Jin’s evolving perspective on animals and his growing acceptance of his diverse classmates. The interactions between the human and animal characters drive the narrative, creating a blend of humor, heartwarming moments, and educational content that appeals to a wide audience.