The game is set in an alternate reality, in which Tokyo is invaded by hordes of demons. You play the role of a young man who lives in an underground shelter and is training to become a demon hunter with help of special programs. One day, during a training, one of the programs goes berserk, and as a result you are thrown into the world where you must fight for your life against vicious demons.

Giten Megami Tensei: Tokyo Mokushiroku is a non-canonical part of Megaten universe, featuring recurrent setting and story elements of the franchise. Like in classic Shin Megami Tensei games, the largest part of the game is spent in 3D dungeons, which are viewed from first-person perspective. The battle system introduces some unusual elements: enemies are visible before the actual battle begins, and during your dungeon exploration, you will be sometimes attacked from different sides. You will have to turn around to face the enemy in real time, but the game will be paused when you select commands from menu, in a traditional turn-based fashion.

In 199X, Tokyo was destroyed by ICBMs, resulting in a nuclear holocaust. Some people with foresight had built underground shelters and survived the Great Cataclysm, while demons began to rampage on the ground. People in the underground shelters still need to defend against demon invasion, and thus an organization called Devil Busters have formed. Around 20 years passed, and a new generation has grown up in the shelters...

In Giten Megami Tensei, you play as Ayato Katsuragi, a devil buster who was born and raised in the Hatsudai Shelter. Ayato joins the force after his parents are brutally murdered by demons. He passes the exam with his friend Yuuka Tachibana, the reincarnation of Ishtar. Later, the shelter is attacked by demons, Ayato is possessed, and Yuuka is killed by demons. She is divided into eight pieces and gives one to each of his comrades. Ayato escapes and swears to get the body parts back.

The story is structured somewhat episodically. Ayato joins with Rui Asuka, Tatsuya Hayasaka, Emi Kirishima, Yoshio Nishino, Isamu Yamase, Tetsuya Sonoda, Kouki Kamikawa, Kazumi Yamada, Sanshirou Souma, and Doctor Kusaka. Many end up dead at one point in the story.