The story of Nier Replicant begins in the summer of 2053 in the ruins of an unidentified city. A prolonged snowstorm envelops the region, trapping the few survivors in a gripping cold with little shelter and minimal food. Two who have made it through the onslaught of climate change lie hunkered down in the remains of a grocery store - a boy and his sister. The girl suffers from an uncontrollable cough, while her weary brother weighs a fateful decision. The mysterious book lying on the ground between them taunts the brother with its power to help. He only needs to hand over his soul to receive the tome's power. A number of monsters known as Shades appear and the brother fights them off to protect his sister with the help of the book. After defeating the Shades the child grows sicker.

The story continues some 1,412 years in the future where a boy named Nier endures a similar struggle. His only sister has succumbed to a violent cough and must remain in bed while he searches for a cure. Though much time has passed, the world in which this brother and sister resides is, in many ways, one of a simpler time. Villagers live in modest homes and work together to ensure a better life for their community. The entire village knows of young Yonah's illness, and lends their support by hiring Nier for numerous odd jobs and errands. Some would say the work is beneath a man of his caliber, but he holds his head high and does whatever he can to provide for his sister, all the while hoping that the village's wisest member, Popola, and her twin sister Devola can discover a cure.