Persona: Trinity Soul takes place approximately ten years after the end of Persona 3. It is set in Ayanagi City, a city located near the Sea of Japan, where the police force is investigating several "Reverse" cases, wherein the victims are turned inside-out. Ten years ago, Ayanagi city had been subjected to a sudden outbreak of Apathy Syndrome, which the city has since recovered from.

In the midst of the crisis, two brothers named Shin and Jun Kanzato move back to Ayanagi to see their elder brother Ryō, who is now the Superintendent of the Ayanagi City Police. It has been ten years since the three siblings last met with each other.

It was said that the mysterious incidents in Ayanagi City were linked to covert testing conducted under Keisuke Komatsubura's watch, which tried to locate all known Persona users and find the strongest by weeding them out via Persona experiments before it was disbanded.