"Interviews with Monster Girls" is set in a world where demi-humans, known as "Ajin," coexist with ordinary humans. These Ajin possess unique traits and abilities tied to their specific species, such as vampires, dullahans, succubi, and snow women. The story centers on Tetsuo Takahashi, a high school biology teacher with a deep fascination for Ajin and their biology. His curiosity leads him to conduct interviews with three Ajin students at his school—Hikari Takanashi, a lively and energetic vampire; Kyouko Machi, a shy and reserved dullahan; and Yuki Kusakabe, a snow woman struggling with her cold aura. Additionally, the narrative includes Sakie Satou, a succubus and fellow teacher who faces challenges due to her species' inherent traits.

The series explores the daily lives of these Ajin as they navigate societal perceptions, personal insecurities, and the complexities of their unique abilities. Hikari, for instance, grapples with her vampiric need for blood while maintaining her cheerful demeanor. Kyouko deals with the awkwardness of her detachable head and the emotional barriers it creates. Yuki struggles to control her freezing aura, which inadvertently affects those around her. Sakie, meanwhile, faces the social stigma of being a succubus, which complicates her interactions with colleagues and students.

Takahashi's role as an empathetic and supportive figure helps the Ajin students and Sakie confront their challenges. His genuine interest in understanding their experiences fosters a sense of acceptance and belonging among the group. The narrative balances lighthearted moments with thoughtful exploration of themes such as identity, acceptance, and the importance of empathy in bridging differences. Through its portrayal of Ajin and their interactions with humans, the series highlights the universal desire for connection and understanding, regardless of one's nature.