The novel follows the adventures of John Carter, a Confederate veteran from Virginia who, after a mysterious encounter in a cave, finds himself inexplicably transported to the planet Mars. On Mars, he discovers that he has greater strength and agility due to the lower gravity of the planet. He soon becomes embroiled in the conflicts and politics of this alien world.

On Barsoom, Carter encounters various alien races, including the Tharks, a green-skinned and four-armed warrior race, and the red-skinned inhabitants of Helium. He also meets the titular princess, Dejah Thoris, of the city-state of Helium. Dejah Thoris is captured by the Tharks, and John Carter, with his newfound abilities, embarks on a mission to rescue her.

As the story unfolds, Carter becomes a central figure in the wars and power struggles between the different Martian city-states. He also discovers the existence of ancient technologies and a dying planet in need of saving.