The game is set in a world called Legaia, home to humans and to entities called Seru that can fuse with people to grant them extraordinary powers. Humans and Seru once lived in harmony, but about ten years before the story opens, a mist blanketed the world and drove the Seru mad on contact, twisting them into monsters that turned on humanity until civilization nearly fell. As the tale begins, the survivors huddle together in remote regions, hiding from the Mist.
The story follows three heroes — quiet Vahn, the wild child Noa, and the gruff warrior monk Gala — on a quest to restore ten Genesis Trees across Legaia and drive back the Mist. Each has joined with a Ra-Seru, beings that bestow Seru-like powers yet remain immune to the Mist. Crossing three continents, they revive Genesis Trees to clear the Mist from small areas and destroy the Mist Generators that produce it, repeatedly clashing with Songi, Gala's old rival, who has bonded with a Seru and is slowly mutating into a monster.
Near the end, in the ruined city of Conkram, the heroes travel back in time and learn that the Mist was engineered as a biological weapon by Prince Cort — Noa's brother. Unable to save Conkram or Noa's parents in the past, they return to the present, destroy the last Mist Generator, and defeat Cort, who secretly merges with the colossal Seru Juggernaut. After Juggernaut devours Vahn's hometown of Rim Elm, the heroes journey inside it to defeat Cort once more, ending with Juggernaut's destruction, Cort's rebirth as a baby in Noa's care, and the restoration of Rim Elm and its people.