Serph, leader of the Embryon, wanders aimlessly through the lifeless streets before him. In the Junkyard, his Tribe fought a gruesome war, hoping the light of heaven would relieve their suffering. In the end, Serph’s world vanished, along with the comrades who stood by his side. All that awaited him in Nirvana were endless streets littered with the silent remains of human statues.
Guards in white appear through clouds of dust, threatening to arrest Serph as an unauthorized Avatar Tuner. Serph notices the Karma Temple's insignia on their equipment as they throw it aside and transform into hideous demons. The water crown's power washes over Serph, and realizes the Atma was not simply a nightmare of 'The Junkyard'. Nothing has changed but his surroundings... Devouring others is the only way to survive. What awaits Serph beyond Nirvana? A glorious paradise, or a sea of blood-soaked corpses?
After God felt Sera's sadness, he caused the sun to turn black and flooded the world with data, turning people into stone. Due to Sera's direct link with God, the data of many of those who perished was "copied" into the Junkyard, creating new AI programs.
Jenna Angel later used the Junkyard as a testing ground for her demon virus. Sera entered the virtual world to try and stop her, and the human personalities of the AIs within began to awaken.
In the future, a mysterious disease that causes the human body to slowly turn to stone is discovered. This is called the Cuvier Syndrome, and is found to be originating from corrupted data emanating from the Sun, also known as God.
A group of scientists found the Karma Society to study God. Children who have the psychic ability to speak with God are located, and the scientists create a machine to enhance their power. However, many of the children are driven insane from prolonged exposure to God and die. Only one survives- candidate number 19, a girl named Sera.
One of the scientists rebels against the project because of the upsetting treatment of the test subjects. A fight ensues, and Sera accidentally witnesses one of her caretakers be killed in the conflict. As she begins to cry so does God, and he rains his fury down upon the Earth.
Serph, the protagonist from the first installment returns once more in Digital Devil Saga 2, the leader of the Embryon, the winning tribe from The Junkyard. He is accompanied by the original Embryon team comprising of its members, Argilla, Gale and Cielo excluding Heat and Sera who were both separated from them upon reaching Nirvana.
With plans on entering The Karma City, Roland, a newcomer and a playable character accompanies them together with the group he leads. "The Lokapala", a resistance force against "The Karma Society". Fred, the son of the former leader of The Lokapala also joins the cast.
The Embryon escaped the deletion of the Junkyard in the finale of Digital Devil Saga and the data that comprised their egos were converted into flesh and bone bodies by the will of Sera and the power of God.
The soundtrack was entirely composed by Shoji Meguro except for the ending song composed by nao and arranged by Koichi Yusa. The soundtrack was released on December 22, 2005 by Five Records as discs 3&4 of the 4-disc set DIGITAL DEVIL SAGA ~Avatar Tuner~ 1 & 2 Original Sound Track: Integral. However, the soundtrack is missing several tracks notably the piano version of Atonement and the battle theme which is played against Jack Frost and Omoikane.
A CD containing a selection of tracks was also released with copies of the US and European (collector's edition) versions of the game.