Genshiken follows the lives of a group of college students drawn together by their shared hobbies, and the trials and adventures associated with being otaku. The story begins with the introduction of Kanji Sasahara, a shy, confidence-lacking freshman who on club day at university, decides to join a club he would actually enjoy, Genshiken. Over his four years at Shiiou University, Sasahara comes to accept himself for who he is and loses the inhibitions and guilt he once felt and associated with otaku culture, becoming an enthusiastic clubmember, and for a time, a capable club president. As the story of Genshiken progresses, focus is also placed on Saki Kasukabe, a determined non-otaku who initially struggles to drag her boyfriend out of the club, and Chika Ogiue, a self-professed otaku-hater who feels a deep-seated shame and self-loathing toward her own interests and hobbies.

During the course of the series, the reader bears witness as the group grows in its cohesiveness over time, and bonds form between the characters as they begin to see themselves as more than fellow club members, but friends as well. In this context, club activities such as group outings, the biannual pilgrimage to Comifes, and even simply hanging out in the clubroom, allow the characters' complex relationships to grow into friendship, infatuation, and at times, even love. While a few of them never quite see eye-to-eye about their interests or the lives they lead, they are held together by the bonds of friendship that they share.