"Tomo-chan Is a Girl!" is a romantic comedy manga that centers on the relationship between Tomo Aizawa and Junichirou Kubota, childhood friends who have known each other since elementary school. Tomo, a tomboy with a strong, athletic personality, has always been treated as "one of the guys" by Jun, who remains oblivious to her feelings for him. Despite her efforts to convey her femininity and romantic interest, Jun consistently fails to recognize her as anything more than a close friend, leading to a series of humorous and heartfelt misunderstandings.

The narrative explores the dynamics of their relationship as Tomo navigates the challenges of expressing her feelings while Jun gradually begins to see her in a new light. Supporting characters, such as Misuzu Gundou, Tomo's sharp-tongued and calculating best friend, and Carol Olston, a cheerful and airheaded classmate, add depth to the story. Misuzu often provides sarcastic commentary and schemes to push Tomo and Jun closer, while Carol's carefree nature contrasts with the more serious tones of the main plot.

The manga balances comedic moments with genuine emotional development, as Tomo and Jun's bond evolves from a platonic friendship to a deeper, more nuanced connection. The story delves into themes of self-discovery, communication, and the complexities of relationships, all while maintaining a lighthearted and engaging tone. Through its episodic structure, the series captures the ups and downs of adolescence, blending humor with relatable struggles and heartfelt moments.