"Ms. vampire who lives in my neighborhood" centers on the daily life of Sophie Twilight, a socially awkward vampire who has chosen to live peacefully among humans in modern Japan. Unlike traditional depictions of vampires, Sophie does not hunt humans for blood; instead, she sustains herself by purchasing blood packs online. Her life takes an unexpected turn when she encounters Akari Amano, a cheerful and curious middle school girl who becomes fascinated with Sophie after discovering her true identity. Despite Sophie's initial reluctance, Akari insists on becoming her friend and frequently visits her home, often bringing along her equally eccentric friend, Hinata Natsuki.

The series explores the growing bond between Sophie and Akari, blending slice-of-life elements with supernatural themes. Sophie's interactions with Akari and Hinata gradually help her overcome her social anxieties, while Akari's relentless optimism and curiosity bring a sense of warmth and humor to their relationship. The narrative also introduces other supernatural characters, such as Ellie, a half-vampire who idolizes Sophie, and Yuki, a werewolf who works as a maid and harbors a crush on her. These characters add depth to the story, creating a dynamic and interconnected world where humans and supernatural beings coexist.

Throughout the series, the focus remains on the lighthearted and often comedic moments of their daily lives, with occasional glimpses into the challenges of being a vampire in a human-dominated world. Sophie's struggles with her identity and her desire to live a normal life are juxtaposed with Akari's unwavering acceptance and enthusiasm, creating a heartwarming and engaging dynamic. The anime balances humor, friendship, and supernatural elements, offering a fresh take on the vampire genre while maintaining a relaxed and enjoyable tone.