In 19th-century England, a youth named Dio Brando is adopted by the wealthy George Joestar to repay Dio's father for seemingly saving his life. Jonathan Joestar, who aspires to become a gentleman, finds himself shunned by his family and friends as part of Dio's plot to take the Joestar fortune for himself. But after Jonathan overpowers Dio in a battle, the latter decides to bide his time. Meanwhile, Jonathan develops an interest in a mysterious stone mask that belonged to his mother. It is later revealed to be an ancient artifact that grants the wearer immortality.
Despite how friendly the two seem to become as they grow up, Jonathan learns seven years later that Dio has been poisoning his father. Jonathan's search for an antidote takes him to London's dodgy Ogre Street, where he befriends a bowler-hat-wearing mugger named Robert E. O. Speedwagon. Speedwagon leads him to Dio's accomplice: a black market
apothecary named Wang Chan. At the same time, Dio intends to arrange a freak accident to kill Jonathan with the stone mask and tests the mask on a drunkard. However, the mask instead turns the drunk into a powerful vampire who nearly kills Dio before being destroyed by sunlight. Returning to the mansion and finding his scheme exposed, Dio attempts to kill Jonathan and use his blood with the mask to become a vampire. Though George takes a fatal wound, Dio succeeds in using the mask to become a vampire. Jonathan eventually defeats Dio by setting the family's mansion on fire.
Three days after the incident, Jonathan awakens from a coma to find himself in Erina's care, and the two rekindle their relationship. However, an encounter with a strange Italian man named William Anthonio Zeppeli introduces Jonathan to a mysterious power known as Hamon, and Jonathan agrees to learn to use it upon hearing that Dio has survived. Jonathan and Zeppeli travel to Windknight's Lot, where Dio is creating an army of zombies. Dio also uses his power to resurrect Queen Mary's protectors Bruford and Tarkus to fight Jonathan, a battle which ends with Zeppeli's death. Later, joined by Zeppeli's fellow Hamon users, Jonathan confronts Dio and manages to send Hamon directly into him, dissolving his body. The Stone Mask is destroyed, and Dio's zombie army is defeated.
Soon after, Jonathan marries Erina, and they head off on a honeymoon cruise across the Atlantic Ocean. But to his horror, Jonathan learns that Dio survived by severing his own head and intends to transplant himself onto Jonathan's body. After being fatally wounded by Dio and Wang Chan, Jonathan uses his remaining Hamon to cause the ship's engine to overload. While Jonathan traps Dio in his arms as they are dragged into the depths, Erina escapes in Dio's coffin along with a dead passenger's baby girl. Rescued near the Canary Islands a day later, and still bearing Jonathan's unborn child, Erina vows to pass on the truth of Jonathan's life to her child and the generations to follow.