America, 1938. Robert E. O. Speedwagon, his foundation, and Straits venture to Mexico to gather more information about the enigmatic Stone Masks. While excavating the ruins, Speedwagon's men are slaughtered by Strait's sudden betrayal and his lust for power, putting Speedwagon in grave danger.

Meanwhile, at the behest of their ally Speedwagon, Joseph Joestar and his grandmother Erina Pendleton have moved to New York City from London. In this new environment, trouble is always around the corner for the hotheaded man, as cultural differences and stubborn citizens spark frequent fights. However, through the power of his "Ripple"—an ability said to be inherited from his grandfather Jonathan Joestar—he defeats foes effortlessly.

One night at a downtown Italian restaurant, Joseph and Erina are provoked when an enormous man across their table taunts them. A proper gentleman from the same table apologizes and informs the two of a disturbing rumor: Speedwagon has been murdered. With an uncertain future, Joseph's bizarre adventure begins, meeting like-minded yet brawny individuals and unearthing remote mysteries along the way.