Ashitaka is expected to be the next leader of his clan. However, a possessed Nagonomori terrorizes the land and attacks three girls on their way back to the village and Ashitaka has no choice but to attack the creature. Essentially attacking Tatari-gami however is never a wise idea and as punishment by Tatari-gami, Ashitaka is marked and fated to die. Determined to meet his fate and spare his village any potential harm, Ashitaka sets out on a journey with Yakuru (his mount) to determine the source of the unusual lump discovered in the disintegrated remains of Nagonomori.

Tatara village is an unusual place where primitive fire arms are being developed. The surrounding land's trees have all been cut down to make space for further development. However, Shishigami's creatures by their very nature are trying to replant the trees which were lost. Eboshi, leader of Tatara however uses her firearms to scare away the Shojou from performing their duty and replanting the trees.

San, a young girl who was raised by Moro-no-kimi is outraged by the destruction of the land by Eboshi and is determined to kill her. With the help of Moronokimi and two Moronoko, San attacks the village in an effort to kill Eboshi. Ashitaka, currently in the village which was also the source of the unusual metal lump (primitive iron slug) in Nagonomori's body interferes in the fight between Eboshi and San and claims San's life as his in exchange for sparing Eboshi. Ashitaka is mortally wounded when saving San, who in return takes him to the place where Shishigami comes down to the earth during the new moon. Shishigami heals Ashitaka of his wound but does nothing about the tatari or curse infecting Ashitaka.

Eboshi, determined to go ahead with her village's continued industrialization determines to kill Shishigami in an effort to show the people that the God has no true power, and in order to get rid of Shishigami's servants from working against her plans. Aided by Jiko?? who wants Shishigami's head for personal reasons, Eboshi learns the location where Shishigami walks on the earth. Stripping her village of the warriors, Eboshi leaves a group of determined women to guard the town while she tries to kill Shishigami. However, a group of Samurai from a neighboring town attack and Tatara is in dire straits...