In the year 2138, virtual reality gaming is booming. Yggdrasil, a popular online game is quietly shut down one day. However, one player named Momonga decides to not log out. Momonga is then transformed into the image of a skeleton as "the most powerful wizard." The world continues to change, with non-player characters (NPCs) beginning to feel emotion. Having no parents, friends, or place in society, this ordinary young man Momonga then strives to take over the new world the game has become.

In 2012, the world allegedly comes to an end at the hands of a human-made virus, ravaging the global populace and leaving only children untouched. It is at this time that vampires emerge from the recesses of the earth, likely followed by age-old horrors of the dark thought only to be myth. The vampires sweep the earth and claim it in a single violent stroke, subjugating the remnants of humanity and leading them beneath the surface to safety. This "protection" comes at the price of donating blood to their captors. At the age of twelve, Yūichirō and his friend and fellow orphan Mikaela plotted to escape along with the children in Hyakuya Orphanage. However, this resulted in their deaths and Mikaela sacrifices himself in order for Yūichirō to escape and be saved by members of the Moon Demon Company, an extermination unit of the Japanese Imperial Demon Army. Four years later, Yūichirō dedicates his life to destroy vampires and seek revenge against them for murdering his "family".

Oreki Houtarou is a minimalistic high school boy. One day, he joins the Classic Literature Club at his elder sister's request. There he meets Chitanda Eru, Fukube Satoshi, and Ibara Mayaka. Chitanda is a calm beautiful girl but she turns into an embodiment of curiosity once she says, "I'm curious." Fukube is a smiling boy with a fantastic memory who calls himself a database. Ibara is a short girl and is strict with others and herself. They begin to investigate a case that occurred 45 years ago. Hints of the mystery are buried in an old collection of works of the former members of Classics Club. The collection is titled "Hyouka."

Being just a normal student without a special talent, Makoto Naegi wins a lottery to attend the prestigious Hope's Peak Academy where only the top prodigies attend. However, instead of this being the beginning of a wonderful high school life, it's a ticket to despair, because the only way to graduate from Hope's Peak Academy is to kill one of your fellow students or be one of their victims.