"ESPer Mami" centers on Mami Sakura, a middle school girl who unexpectedly gains psychic powers after a mysterious encounter with a UFO. These abilities, which include telekinesis, teleportation, and telepathy, initially seem like a blessing but quickly complicate her life. Mami struggles to balance her newfound powers with her everyday responsibilities, often finding herself in humorous and chaotic situations as she attempts to use her abilities to help others while keeping them a secret from her family and friends.

The narrative unfolds episodically, with each episode presenting a new challenge or dilemma for Mami to navigate. Her powers frequently lead to unintended consequences, forcing her to think creatively to resolve the problems she inadvertently creates. Mami's best friend, Kazuya, becomes her confidant and occasional accomplice, providing moral support and helping her manage the fallout of her psychic mishaps. The series also introduces recurring characters, such as Mami's rival, Ayako, who often complicates Mami's efforts, and various supernatural entities that test her abilities.

As the story progresses, Mami's powers evolve, and she encounters increasingly complex situations that challenge her understanding of responsibility and morality. While the tone remains lighthearted and comedic, the series occasionally delves into more serious themes, such as the ethical implications of using psychic abilities and the importance of honesty and integrity. Mami's journey is one of self-discovery, as she learns to harness her powers responsibly while maintaining her relationships and navigating the trials of adolescence. The series blends humor, fantasy, and slice-of-life elements, creating a unique narrative that explores the intersection of the ordinary and the extraordinary.