"Kotoura-San" centers on Haruka Kotoura, a young girl cursed with the ability to read minds, a power she has possessed since childhood. This ability isolates her from others, as her unintentional exposure of people's hidden thoughts and secrets leads to mistrust and alienation. Her family falls apart due to her revelations, and she becomes a social outcast at school. By the time she enters high school, Haruka has resigned herself to a life of solitude, believing her power will only bring pain to herself and others.

Her life takes a turn when she meets Yoshihisa Manabe, a carefree and eccentric classmate who remains unfazed by her mind-reading ability. Instead of shunning her, Manabe embraces her power, finding it fascinating and even useful. His unwavering acceptance and humor provide Haruka with the first genuine connection she has ever experienced. The two form a close bond, and Manabe encourages her to open up to others, gradually helping her rebuild her confidence and social life.

As the story progresses, Haruka and Manabe navigate the challenges of high school together, forming a club called the ESP Research Club with their classmates Yuriko Mifune, a sharp-tongued but kind-hearted girl, and Daichi Muroto, a timid yet loyal friend. The club becomes a space for Haruka to explore her abilities and develop friendships, though her mind-reading often leads to comedic and dramatic situations as she uncovers the hidden thoughts and emotions of those around her.

The narrative balances lighthearted moments with deeper explorations of Haruka's struggles, including her lingering trauma from being abandoned by her mother, who could not cope with her daughter's abilities. The series also delves into the complexities of human relationships, as Haruka learns to navigate the fine line between knowing too much and understanding the true intentions behind people's thoughts. Through her interactions with Manabe and her friends, Haruka begins to heal and find a sense of belonging, ultimately embracing her power as a part of who she is.