Set in 1996, Megami Ibunroku Persona centers around the protagonist and his classmates at St. Hermelin High School in Mikage-cho (Lunarvale in Revelations: Persona). Hidehiko Uesugi talks all of his friends into playing a game called "Persona", which is played much like the ritual game "Bloody Mary". While playing, the students lose consciousness and meet Philemon, who gives them the ability to summon reflections of their personalities, which are known as Personas.

A short time later, the protagonist and several of his friends go to visit Maki Sonomura, who is ill and bed-ridden. During their visit, they discover that the town is changing and demons are roaming the streets. The party is told by Maki's mother, an engineer working for SEBEC, that the culprit behind the incident is Takahisa Kandori, president of the company.

After taking Maki's mother to the school (the only place in town safe from demons), the protagonist's actions decide the course of the story. If the protagonist opts for going after Kandori, it'll start the SEBEC Chapter which is the main storyline of the game. Alternatively, the protagonist may opt for investigating a series of incidents that occurred in the school eight years ago and start the Snow Queen Quest, an alternate storyline unrelated to the SEBEC incident.