In Muromachi Japan, an Emishi village is attacked by a demon.

The last Emishi prince, Ashitaka,

kills it before it reaches the village, but its corruption curses his arm in the battle. The curse gives
his arm superhuman strength, but will eventually kill him. The villagers discover that the demon
was a boar god, Nago, corrupted by an iron ball lodged in his body. The village's wise woman
tells Ashitaka that he may find a cure in the western lands Nago came from but he cannot return
to his homeland.
Heading west, Ashitaka meets Jiko-bō, a wandering monk, who tells Ashitaka he may find help
from the Great Forest Spirit, a Kirin-like creature by day and a giant "nightwalker" by night.
Nearby, men herd oxen to Irontown, led by Lady Eboshi, when they are attacked by a wolf pack
led by the wolf goddess Moro. Riding one of the wolves is San, a human girl. Later, Ashitaka
discovers two injured Irontown men, and sees San and her wolf pack; he greets them, but they
leave. He carries the injured men through the forest, where he encounters many kodama, and
glimpses the Forest Spirit.
In Irontown, Ashitaka learns Eboshi has built the town by clearcutting forests to
claim ironsand and produce iron, leading to conflict with the forest gods towards which she has
no mercy. The town is a refuge for social outcasts, including former brothel workers and lepers,
whom Eboshi employs to manufacture firearms to defend against the gods; Nago was turned into
a demon by one of Eboshi's guns. Eboshi also explains that San, self-dubbed Princess
Mononoke, was raised by the wolves as one of their own and resents humankind.
San infiltrates Irontown to kill Eboshi, but Ashitaka intervenes, knocking them both unconscious.
As he leaves, he is shot by a villager (unintentionally), but the curse gives him the strength to
carry San out of the village. San awakens and is about to kill the weakened Ashitaka, but
hesitates when he tells her that she is beautiful. She takes him to the forest, and decides to trust
him after the Forest Spirit saves his life.
A boar clan led by the blind boar god Okkoto attacks Irontown to save the forest. Eboshi
prepares for battle and sets out to kill the Forest Spirit under Jiko-bō's supervision, who is
working for the government. Eboshi intends to give the god's head to the Emperor of Japan in
return for protection from local daimyō; according to legend, the Forest Spirit's head grants
immortality.
In battle, the boar clan is annihilated and Okkoto is corrupted by gunshot wounds. Jiko-bō's men
disguise themselves in boar skins and trick the rampaging Okkoto into leading them to the Forest
Spirit. San tries to stop Okkoto, but is swept up in his demonic corruption. Moro intervenes and
Ashitaka dives into the corruption to save San. However, Ashitaka's infection is accelerated, and
San too is cursed.
The Forest Spirit kills Okkoto and Moro, and during its nightwalker transformation, Eboshi
decapitates it. It bleeds ooze that instantly kills life as it searches for its head, which Jiko-bō has
stolen. The forest and kodama begin to die, and Moro uses her last moment to bite off Eboshi's
right arm. Ashitaka follows Jiko-bō to Irontown after bandaging Eboshi and convincing San to
accompany him. Ashitaka and San battles with Jiko-bō to retrieve the head and return it to the
Forest Spirit. Ashitaka, San and the land are healed, but the Forest Spirit dies. Ashitaka will help
rebuild Irontown, but tells San he will visit her in the forest. Eboshi vows to build a better town as
the forest begins to regrow.