"Tonari no 801-chan" is a comedic slice-of-life manga that humorously explores the dynamics of a romantic relationship between a young man and his otaku girlfriend. The protagonist, a salaryman referred to as "Ranmaru," lives a relatively ordinary life until he begins dating a fujoshi named Yūko. Yūko is deeply immersed in the world of boys' love (BL) manga and doujinshi, often fantasizing about romantic relationships between male characters, including Ranmaru and his male acquaintances. Her obsession with BL frequently leads to awkward and comedic situations, as she projects her fantasies onto real-life interactions, much to Ranmaru's embarrassment.

The narrative primarily revolves around the couple's daily life, highlighting the contrast between Ranmaru's reserved, grounded personality and Yūko's exuberant, imaginative nature. Yūko's passion for BL often disrupts their relationship, as she becomes overly enthusiastic about creating scenarios involving Ranmaru and other men, which he finds uncomfortable. Despite these challenges, the series portrays their relationship as one built on mutual affection and understanding, with Ranmaru gradually becoming more accepting of Yūko's interests, even if he remains exasperated by her antics.

The manga also delves into the broader otaku culture, particularly the fujoshi subculture, through Yūko's interactions with her friends and her participation in events like Comiket. These elements provide insight into the creative and social aspects of fandom, while also serving as a backdrop for the couple's comedic misadventures. The series balances humor with moments of genuine warmth, offering a lighthearted yet insightful look at the complexities of relationships and the quirks of otaku life. The characters are portrayed with a mix of exaggeration and relatability, making their interactions both entertaining and endearing.