A prologue set in a snowstorm in 2049 shows a man named Nier defending his sick young daughter Yonah from ethereal monsters inside a ruined grocery store. The game then leaps 1,312 years into the future, where what appear to be the same two characters live in a primitive village raised atop the ruins of an old town, surrounded by the wreckage of a more advanced age and roamed by hostile creatures called Shades. With Yonah dying of a terminal affliction known as the Black Scrawl, Nier sets out to find a cure, soon joined by a talking tome named Grimoire Weiss, the hot-tempered swordswoman Kainé, and Emil, a blindfolded boy whose gaze turns onlookers to stone. When a master Shade called the Shadowlord — bearer of his own book, Grimoire Noir — carries Yonah away, the quest turns to hunting him down.
Five years later, after assembling a key from defeated Shades, Nier's group confronts the truth: over thirteen centuries earlier, dying humanity split its souls (Gestalts) from its bodies and created disease-resistant clones called Replicants, intending one day to recombine them — but the Replicants developed their own identities while the Gestalts, now Shades, grew violent. The Shadowlord proves to be the Gestalt of the Nier from the prologue, who fused his own Yonah with the Replicant one to save her. After Emil sacrifices himself, the group defeats the Shadowlord and the original Yonah, hearing her Replicant counterpart within her, willingly relinquishes the body so Nier and his Yonah can reunite. Later playthroughs unlock Kainé's tragic backstory, let the player understand the Shades as sentient beings defending their own, and offer a final, wrenching choice to save Kainé — one ending of which erases Nier from everyone's memory and deletes the player's save entirely.