Akemi Nakajima is a high school student and a computer programming prodigy who created a program that can summon demons from Makai. His original intentions for the program were to gain revenge on a classmate who had fought with him. He brings his friend Yumiko Shirasagi, a transfer student that became interested in Nakajima and found to be the reincarnation of the goddess Izanami, to combat the malicious demons he unleashed. Nakajima had been tricked into summoning a demon named Loki with his program, whereas the American computer genius Isma Feed has summoned the demon Set in order to use its power. The game is assumed to take place after the first two Digital Devil Story novels when the demons Loki and Set have been defeated, and it diverges from the original ending of the third novel. The demon Lucifer has revived them, though, in order to prepare to invade the human world once again.

The story begins with two young men in an underground shelter playing a video game called Devil Busters, which retells the opening events of Digital Devil Story: Megami Tensei. After being the game's boss, they release the demon Pazuzu, who claims that the two men are the Messiahs destined to be the saviors of mankind. He grants the Hero the ability to summon and talk to demons, and his friend the gift of magic. Pazuzu gives them the mission of destroying the demon lords that have taken control of Tokyo, starting with Bael, the demon that sealed him inside Devil Busters. The heroes venture outside the shelter, and they are recognized as messiahs by the Church of Messiah. Upon reaching Tokyo Tower, however, the heroes find a witch who was also named a messiah by Pazuzu, but claims he has been manipulating them for his own gain. The friend refuses to believe that Pazuzu is using them. In order to progress in the story, the player has to side with the witch, causing the friend to leave and become his enemy.

It is Tokyo in the year 2050 where terrorists are running wild in the streets, and only one armored police officer is fast enough to hunt them down.

The game takes place in the near-anarchic future of the year 2097, in which the world's economy has been devastated, governments have collapsed, and organized crime has gained dramatic influence. In X-Kaliber 2097, the player guides a swordsman named Slash through a side-scrolling environment. Boss encounters take place as one-on-one matches in the style of versus fighting games.