Set in the United States in 1890, it stars Johnny Joestar, a paraplegic former jockey who desires to regain the use of his legs, and Gyro Zeppeli, a disgraced former executioner who seeks to win amnesty for a child on death row.

Though they begin the race as rivals, Johnny and Gyro become friends as they travel through the wilderness while fending off various assassins, terrorists, outlaws, and other violent competitors.

Eventually, Valentine succeeds in taking Johnny and Gyro's corpse parts, seizing Diego's eye soon afterward with the aid of his dimension-traversing Stand, Dirty Deeds Done Dirt Cheap.

Mourning his mentor and friend, Johnny realizes how to achieve the perfect form of the Spin technique, enhances his Stand, and overwhelms Valentine with his new power.

Pursuing the thief into the final stage of the Steel Ball Run, Johnny is shocked to find that it is an alternate instance of Diego Brando taken from a parallel dimension by Valentine, wielding a time-stopping Stand known as The World.

Valentine's death is covered up as retirement from public life, with concerns over the race placated by the donation of the prize money to charitable causes.

[7] Because the series follows a race across America, Araki had to split his research into three trips: one from the West Coast to the deserts, one from the Great Plains to the Mississippi River and Chicago, and one to New York.

The feeling of distance made him think that if an enemy had approached, the open landscape would have meant that he could not have escaped due to a lack of places to hide, an experience he found useful when drawing the manga.

[7] Valentine was created as part of Araki noticing more and more that good and evil is not always easily distinguishable and taking a greater interest in the motivations for people who do bad things.

recommended Steel Ball Run as a good place to start for people who have not read previous parts, due to how it effectively serves as a reboot of the JoJo's Bizarre Adventure series, and appreciated how its move to the monthly seinen magazine Ultra Jump enabled Araki to write longer stories and depict things that would have been difficult to do in a shōnen manga magazine.

[54] Anime News Network called Steel Ball Run an interesting take on the battle manga genre due to its positive portrayal of a hero with a disability, and found it, along with JoJolion, to represent a big shift in the evolution of Araki's art, following his earlier shift from muscle men to thinner characters and fashion.

[7] K. Thor Jensen of Geek.com called the portrayal of Johnny and Gyro's relationship one of the best platonic friendships in comics, citing their transition from rivals to close allies who make sacrifices for one another and help each other with their respective abilities.