During the late 1930s in Chicago, the transcontinental train, Flying Pussyfoot, is starting its legendary journey that will leave a trail of blood all over the country. At the same time in New York, the ambitious scientist Szilard and his unwilling aide Ennis, are looking for missing bottles of the immortality elixir.

The curse of an evil witch turns a plain young hat-maker, Sophie, into an old woman. Sophie runs away to confront the witch and become young again when she rescues a trapped animated scarecrow.

While fighting to save his village from the attack of a demon-god Ashitaka comes in contact with it and is inflicted with a deadly curse. In his search for a cure he is forced to leave his village forever and journey to the forest inhabited by animal gods.