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According to an ancient Japanese legend, mermaid flesh may grant immortality if eaten. However, there is a much greater chance that consumption will lead to death or transformation into a damned creature known as a Lost Soul. Mermaid Saga tells the tale of Yuta, an immortal who has been alive for five hundred years. Throughout the series, he wanders across Japan searching for a cure and meets others whose lives have also been ruined by mermaid flesh.

A personal tragedy causes young forensics investigator Paula to have a breakdown, which results in her admittance to a psychiatric hospital. There, she is pulled into the darkest and most terrifying corners of her mind by a mysterious doctor.