In Japan, 1987,[b] Jotaro Kujo, grandson of Joseph Joestar, has been arrested, and refuses to leave his cell, believing he is possessed by an evil spirit. After being called by Holly, Joseph's daughter and Jotaro's mother, Joseph arrives with an associate, Mohammed Avdol. They explain that Jotaro's "evil spirit" is actually a manifestation of his fighting spirit, called a Stand, and reveal that they possess Stands as well. Joseph explains that the sudden appearance of their Stands is caused by the nemesis of his grandfather, Jonathan Joestar: Dio Brando, now referred to simply as Dio. Dio has survived his final battle with Jonathan by decapitating his nemesis's corpse and attaching his own head to it. Now preparing for global conquest, Dio has awoken his own Stand (which awakens the Stands of the rest of the Joestar bloodline due to his use of Jonathan's body) and recruited Stand-using assassins to kill Jonathan's remaining descendants. Soon after, Jotaro uses his Stand, which is later named Star Platinum, to defeat the first of these assassins, a transfer student named Noriaki Kakyoin, before freeing Kakyoin from Dio's control by removing a parasitic flesh bud from him. Holly soon becomes gravely ill due to a Stand manifesting in her, which is slowly killing her due to her reserved personality. With little hesitation, Jotaro, Joseph, Avdol, and Kakyoin begin a journey to Egypt to kill Dio and save Holly's life. On the way, they defeat another brainwashed assassin named Jean Pierre Polnareff who later joins the quest to kill Dio and avenge the death of his sister, whose murderer is among Dio's forces.
Forced to travel on foot after Dio's assassins manage to foil their travel by plane and ship, the group encounter Hol Horse and the murderer of Polnareff's sister, J. Geil, in Calcutta, with Avdol seemingly killed during the confrontation. Polnareff kills J. Geil with Kakyoin's help, and the remaining group travels further into Pakistan. After defeating Geil's mother, a Dio loyalist named Enya, the group reach the Red Sea, where Polnareff learns Avdol faked his death to acquire a submarine that allows them to reach Egypt.
Upon arriving in Abu Simbel, the heroes are joined by Iggy, a Boston Terrier with a Stand of his own, while facing the first of nine Stands named after Egyptian deities (rather than the tarot theme of before). Kakyoin is wounded in the fight, and is taken to a hospital to recuperate. After the group defeats several more Stand users while reaching Cairo, Iggy discovers and leads them to Dio's mansion, with Kakyoin rejoining them. At the mansion's entrance, the party is split up- Jotaro, Joseph, and Kakyoin fight the last of the nine Egyptian god Stands, while Polnareff, Avdol, and Iggy make their way through the mansion. However, one of Dio's servants, Vanilla Ice, kills Avdol and Iggy, both of whom separately sacrifice themselves to save Polnareff. An enraged Polnareff battles Vanilla Ice and discovers that Vanilla Ice has been transformed into a vampire like Dio, a fact that Vanilla Ice himself was unaware of. Polnareff floods the room with light, disintegrating Vanilla Ice and avenging his friends.
Jotaro, Joseph, Kakyoin, and Polnareff ultimately encounter Dio, and escape his mansion. A chase across Cairo follows, leading to Kakyoin confronting Dio and his Stand, The World, whose power Dio has taken great lengths to keep secret (having previously assassinated Enya to keep her from telling the heroes). Though fatally wounded by The World, Kakyoin manages to deduce the Stand's ability to stop time for five seconds and covertly relays it to Joseph in his final moments. Joseph is able to pass it on to Jotaro, but is swiftly killed by Dio, who uses his blood to increase the duration of his ability to nine seconds. With most of his allies dead and Polnareff unconscious, Jotaro is left to fight Dio alone. During the fight, both sides discover that their respective Stands are similar in both range, power, and ability, meaning that Jotaro is able to use The World's time-stopping powers as well. Jotaro first uses this ability to briefly move around while Dio has stopped time, but he learns how to stop time directly when Dio tries to crush him with a road roller. Dio attempts to kill Jotaro with one final kick, but a counterattack from Jotaro splits The World in two, killing it and Dio. Jotaro transfuses Dio's blood back into Joseph and uses Star Platinum to restart his stopped heart (an ability he'd previously used on himself while playing dead during the fight with Dio), reviving him. The two Joestars then expose Dio's corpse to the sun, destroying the vampire for good. Jotaro and Joseph bid Polnareff farewell before returning to Japan, as Holly has made a full recovery.