Mieruko-chan centers on Miko Yotsuya, a high school girl who suddenly gains the ability to see horrifying spirits and grotesque apparitions that are invisible to others. These entities range from unsettling to outright terrifying, often appearing in mundane settings like her school, home, or public spaces. Miko quickly realizes that acknowledging or reacting to these spirits could provoke them, putting her in danger. To protect herself, she adopts a strategy of complete indifference, pretending not to see them despite their disturbing presence.

The narrative explores Miko’s daily struggles as she navigates life while maintaining her facade of ignorance. Her best friend, Hana Yurikawa, remains oblivious to the supernatural and often provides comedic relief with her cheerful and carefree personality. Hana’s obliviousness contrasts sharply with Miko’s constant vigilance, creating a dynamic that balances tension with lighthearted moments. Another key character is Yulia Niguredō, a shrine maiden who also possesses the ability to see spirits. Yulia initially views Miko as a rival but later becomes an ally, offering insights into the supernatural world and occasionally assisting Miko in dealing with the spirits.

As the story progresses, Miko encounters increasingly dangerous and complex spirits, some of which are tied to unresolved human emotions or tragic events. The series delves into themes of fear, resilience, and the unseen burdens people carry, often blending horror with moments of emotional depth. Miko’s determination to protect herself and those around her, despite her fear, forms the core of her character development. The interplay between the supernatural elements and Miko’s personal growth drives the narrative, creating a unique blend of horror, comedy, and slice-of-life storytelling.