"Imōto Sae Ireba Ii" centers around Itsuki Hashima, a light novel author whose life revolves around writing, drinking, and interacting with his eccentric circle of friends. The series blends comedy, slice-of-life, and drama, often delving into the creative struggles and personal lives of its characters. Itsuki, known for his sister-themed novels, is frequently teased by his peers for his peculiar interests, though he insists his work is purely fictional. His closest friends include Nayuta Kani, a prodigious novelist with a blunt personality and a deep affection for Itsuki; Haruto Fuwa, a fellow author and Itsuki's best friend; Miyako Shirakawa, a college student and aspiring writer who often joins their gatherings; and Chihiro Hashima, Itsuki's actual younger sister, who harbors complex feelings toward him.

The narrative explores the dynamics between these characters as they navigate their careers, relationships, and personal challenges. Itsuki's life is often chaotic, with his friends frequently dropping by unannounced, leading to humorous and sometimes poignant interactions. Nayuta's intense personality and unrequited feelings for Itsuki create tension, while Haruto's laid-back demeanor contrasts with his own struggles as a writer. Miyako serves as a grounding presence, offering support and camaraderie, though she too faces her own insecurities. Chihiro's role adds a layer of emotional depth, as her relationship with Itsuki is marked by both affection and unresolved tension.

The series frequently shifts between lighthearted comedic moments and more serious reflections on creativity, ambition, and human connection. Flashbacks and meta-narratives are used to provide insight into the characters' pasts and motivations, enriching the storytelling. The interplay between the characters' professional and personal lives forms the core of the series, offering a multifaceted portrayal of their world. Through its blend of humor and drama, "Imōto Sae Ireba Ii" presents a nuanced exploration of the challenges and joys of creative work and interpersonal relationships.