Many centuries ago in a remote mountain village of Northern Japan, Ashitaka (voice of BILLY CRUDUP) is the last warrior of the dying Emishi clan. A brave young man, he defends his village from a huge boar monster -- a former forest god turned demon. In doing so and by killing it, however, he gets infected by the curse that drove the boar to madness. As a dark scar begins growing on his arm, he leaves his village forever, hoping to find a cure for his malady before it makes him evil and/or kills him.
During his journey toward the West, he encounters various people including peasants, samurai warriors and a traveling monk, Jigo (voice of BILLY BOB THORNTON). After saving the lives of two men, including Kohroku (voice of JOHN DE MITA), after a wolf attack, Ashitaka and his faithful elk eventually arrive in their frontier village, Iron Town.
Run by an ambitious and ruthless leader, Lady Eboshi (voice of MINNIE DRIVER), and her captain of the guards, Gonza (voice of JOHN DI MAGGIO), the town consists of groups of social outcasts -- such as lepers and former prostitutes, including Toki (voice of JADA PINKETT-SMITH) -- who not only forge iron, but also manufacture and continually refine a new weapon, the rifle.
They use those not only to defend their village from other humans, but also from the forest gods who are upset and occasionally attack the villagers for destroying their habitat. Among them is a small pack of gargantuan wolves led by Moro (voice of GILLIAN ANDERSON) and her adopted feral daughter, the human San (voice of CLAIRE DANES), a.k.a. the Princess Mononoke.
Still seeking a cure for his malady that's slowly spreading up his arm, Ashitaka suddenly finds himself in the middle of an epic war, between various humans and the forest gods, including the wise boar, Okkoto (voice of KEITH DAVID), and tries to find a way to bring peace to the troubled land.