Set sometime in classical Japanese history, Ōkami combines several Japanese mythology and folklore to tell the story of how the land was saved from darkness by the Shinto sun goddess named Amaterasu, who took the form of a white wolf with celestial markings covering its fur. It features a distinct sumi-e-inspired cel-shaded visual style and the Celestial Brush, a gesture-system used to perform miracles.

Once upon a time there was a small village called Kamiki Village, where everyone from the villagers to the animals, lived in peace and happiness. But then one day, the legendary monster Orochi, came back to life and put an evil curse on the entire area. Everything that had a bit of life, disappeared from the face of the earth, and in their place was left a dreadful, barren wasteland. Orochi's horrid curse spread all across the land, turning it into a veritable hell on earth, infested with countless monsters roaming the earth. But there was one hope. The majestic, wolf-embodied sun god Amaterasu. One-hundred years ago, Amaterasu used the godly power of the Celestial Brush, to face Orochi. But their battle consumed them both, causing them to disappear from the world, with Amaterasu losing the thirteen Celestial Brush powers in the process. Now in the present, Amaterasu stumbles upon a mysterious fairy sprite named Issun, and together they set out on an adventure, as Amaterasu aims to regain the 13 powers of the Celestial brush and defeat Orochi once and for all.