After finally escaping the confines of Green Dolphin Street Jail, Jolyne Kuujou—alongside her companions Ermes Costello and Emporio Alniño—pursues the villainous priest Enrico Pucci across the state of Florida. Jolyne's allies, Weather Report and Narciso Anasui, struggle to catch up with her in order to help bring an end to Pucci's plot. As both parties pursue the priest, they must battle against Pucci's band of enemy Stand users. While Jolyne's comrades fight for their lives, Pucci races to the Kennedy Space Center. There he hopes to enact his ultimate goal, one he believes God has entrusted to him. He aims to fulfill the will of the Joestars' blood enemy Dio Brando and—by robbing humanity of free will and making them slaves to fate—to create a world where all humans are blissfully happy. Unable to rely on the aid of her comatose father Joutarou, Jolyne must weaponize all she has learned in prison to confront Pucci in a climactic battle while the world itself hangs in the balance.

Kujo Jotaro is a normal, popular Japanese high-schooler, until he thinks that he is possessed by a spirit, and locks himself in prison. After seeing his grandfather, Joseph Joestar, and fighting Joseph's friend Muhammad Abdul, Jotaro learns that the Spirit is actually Star Platinum, his Stand, or fighting energy given a semi-solid form. Later, his mother gains a Stand, and becomes sick. Jotaro learns that it is because the vampire Dio Brando has been revived 100 years after his defeat to Jonathan Joestar, Jotaro's great-great-grandfather. Jotaro decides to join Joseph and Abdul in a trip to Egypt to defeat Dio once and for all.

Thrown into solitary confinement after a daring rescue attempt, Jolyne Kuujou fights to uncover the sinister plot of Whitesnake, an enemy Stand whose mysterious wielder remains unknown to her. Whitesnake's user is actually Enrico Pucci, priest and chaplain of Green Dolphin Street Prison. Pucci shares a deep connection with a villain who once plagued the Joestar bloodline, making his feud with Jolyne and her father, Joutarou, a personal one. Intent on executing the master plan of his deceased friend, Pucci uses the prison and its inmates to fulfill his nefarious schemes. Assisted by fellow prisoners, like Ermes Costello and Foo Fighters, Jolyne battles several enemy Stand users. As the ramifications of Pucci's plot spread beyond the confines of the prison and begin to threaten the rest of the world, Jolyne embraces her family lineage and risks her life to put an end to evil.

Years after an ancient evil was salvaged from the depths of the sea, Joutarou Kuujou sits peacefully within a Japanese jail cell. He's committed no crime yet demands he not be released, believing he's been possessed by an evil spirit capable of harming those around him. Concerned for her son, Holy Kuujou asks her father, Joseph Joestar, to convince Joutarou to leave the prison. Joseph informs his grandson that the evil spirit is in fact something called a Stand, the physical manifestation of one's fighting spirit which can adopt a variety of deadly forms. After a fiery brawl with Joseph's friend Muhammad Avdol, Joutarou is forced out of his cell and begins learning how to control the power of his Stand. However, when a Stand awakens within Holy and threatens to consume her in 50 days, Joutarou, his grandfather, and their allies must seek out and destroy the immortal vampire responsible for her condition. They must travel halfway across the world to Cairo, Egypt and along the way, do battle with ferocious Stand users set on thwarting them. If Joutarou and his allies fail in their mission, humanity is destined for a grim fate.