The game opens on May 1, 2017, when a blackout occurs in LeMU, its communications system go down, and the park springs a leak; portions of it get flooded, blocking the exit and trapping the characters. Due to water pressure, the park is estimated to implode after 119 hours. The pressure also prevents escape by swimming, as it would crush one's lungs. If the player plays as Takeshi, he builds a relationship with Tsugumi, who reveals that she and her pet hamster Chami are carriers of the Cure virus, which has rewritten their genetic code and halted their biological aging. She and Takeshi have sex, and she becomes pregnant. Later, Coco becomes sick. It is revealed that LeMU was created by the Leiblich Pharmaceutical company as a cover for IBF, a research facility underneath the park. IBF developed the deadly virus Tief Blau, and the LeMU disaster was caused when IBF lost containment of it. Coco was exposed to the virus while visiting her father, an IBF researcher. The group goes to IBF in search for a cure, but starts showing signs of Tief Blau. An exception is Tsugumi, as the Cure virus has made her immune; the group injects themselves with her antibodies. They get contact with the surface, and a rescue pod is sent down, but is only able to stay for a short time. Tsugumi leaves to find Chami, who has gone missing; Takeshi chases after her, and saves Sora's data onto a disk to save her memories. Returning to IBF, they have missed the rescue vessel. They find a submarine and escape, but its batteries die; Takeshi exits it, giving it enough buoyancy to save Tsugumi, while he drowns on the ocean floor. Coco dies in IBF, as she had been looking for Pipi, and the rescue team could not find her. If the player plays as the Kid, Sara is trapped in LeMU instead of Coco; the Kid frequently has visions of Coco, but no one else sees her. The group manages to contact the surface, and open and close doors to rooms in LeMU to move the water around, allowing them to escape. After having played the game as both Takeshi and the Kid, the player accesses the final route, where it is revealed that although the events Takeshi experienced took place in 2017, those the Kid experienced were a recreation, and took place in a rebuilt LeMU in 2034. The You of 2017, whose full first name is Yubiseiharukana,[i] had artificially impregnated herself and given birth to Yubiseiakikana,[j] who took the role of You during the recreation. Pipi had escaped LeMU in 2017, carrying with it the disk with Sora's memories and footage of Coco being trapped in IBF. Sara and the Kid are revealed to be Tsugumi and Takeshi's children, and the Kid's real name turns out to be Hokuto.[k] The Kid of 2017, whose name is Ryogo Kaburaki,[l] played the role of Takeshi during the recreation, having stopped aging due to the Cure virus. The recreation was done to line up two points in the fourth dimension, time, to get the attention of the person playing Ever 17; the characters see the player as a 4th-dimensional being, "Blick Winkel", who can move through time; Blick Winkel appearing was what caused Hokuto's amnesia. Yubiseiharukana tells Blick Winkel that they had told her to perform the recreation to save Takeshi and Coco. Blick Winkel travels to 2017, and wakes up Takeshi on the seafloor, forcing him to swim to IBF; inside, he injects Coco with Tsugumi's antibodies. Blick Winkel warns Yubiseiharukana in 2017 to not save Takeshi and Coco immediately, to avoid a time paradox; instead, Blick Winkel has Takeshi and Coco enter cryogenic suspension in IBF. They wake up in 2034, saved. Sora, who now has a robotic body, is given back her memories from the disk, and Yubiseiharukana leaks information about Leiblich, exposing them as the ones behind the Tief Blau outbreak.

After completing his training, UNATCO agent JC Denton takes several missions given by Director Joseph Manderley to track down members of the National Secessionist Forces (NSF) and their stolen shipments of the Ambrosia vaccine, the treatment for the Gray Death virus. Through these missions, JC is reunited with his brother, Paul, who is also nano-augmented. JC tracks the Ambrosia shipment to a private terminal at LaGuardia Airport. Paul meets JC outside the plane and explains that he has defected from UNATCO and is working with the NSF after learning that the Gray Death is a human-made virus, with UNATCO using its power to make sure only the elite receive the vaccine.[28]