"Sakurako-san no Ashimoto ni wa Shitai ga Umatteiru" centers on Sakurako Kujou, a brilliant and eccentric osteologist with a deep fascination for bones, and Shoutarou Tatewaki, a high school student who frequently accompanies her. The series unfolds as a mystery drama, with Sakurako and Shoutarou encountering various cases involving human remains, often leading them to uncover hidden truths about the deceased and the circumstances surrounding their deaths. Sakurako's expertise in analyzing bones allows her to piece together clues that others overlook, while Shoutarou serves as a grounded counterbalance to her unconventional personality, often mediating between her and the authorities.

The narrative is episodic, with each case presenting a self-contained mystery, yet there is an underlying thread that ties the stories together. Sakurako's past and her personal connection to a tragic event gradually come to light, adding depth to her character and explaining her obsession with bones. Shoutarou, on the other hand, grows from a passive observer to an active participant, developing a stronger sense of responsibility and empathy as he assists Sakurako. The series explores themes of life, death, and the lingering impact of the past, often delving into the emotional weight carried by those left behind.

The dynamic between Sakurako and Shoutarou is central to the story, with their contrasting personalities creating a compelling partnership. Sakurako's aloof and sometimes callous demeanor is tempered by Shoutarou's compassion and moral grounding, making their interactions a key element of the narrative. The series balances its darker themes with moments of levity, often through Shoutarou's reactions to Sakurako's eccentricities or the occasional comedic relief provided by secondary characters. While the focus remains on solving mysteries, the emotional resonance of each case and the evolving relationship between the protagonists ensure a cohesive and engaging storyline.