n 1881, Edgar Rice Burroughs is summoned by a telegram from his uncle, John Carter, a former American Civil War Confederate Army captain. On arriving, he's told Carter has died suddenly and has been entombed, unembalmed, in his mausoleum which only opens from the inside. Carter's lawyer explains Burroughs is to inherit everything and that Carter wanted only Burroughs to read his private journal.
In a flashback to 1868 in the Arizona Territory, Union Colonel Powell arrests Carter. Powell, knowing Carter's military background, seeks his help in fighting Apaches. Carter escapes, but fails to get far from the pursuing U.S. cavalry soldiers. Attacked and chased by Apaches, Carter and a wounded Powell hide in a cave which Carter recognises as the object of his search: the ‘Spider Cave of Gold’.
At that moment, a Thern materialises in the cave and, surprised by the two men, attacks Carter with a knife. Carter kills him but accidentally activates the Thern's powerful medallion and is transported to a ruined and dying planet, Barsoom. Because of his thicker bone density and the planet's low gravity, Carter is able to perform feats of incredible strength and leaps. He is captured by the four-armed Tharks and their Jeddak Tars Tarkas.
Elsewhere on Barsoom, the cities of Helium and Zodanga have warred for a millennia. Sab Than, Jeddak of Zodanga, armed with a special weapon obtained from the Thern leader Matai Shang, plots a ceasefire and an end to the war by marrying the Princess of Helium, Dejah Thoris. The Princess escapes and is later rescued by Carter. They and Tarkas's daughter Sola travel to the end of a sacred river to find a way for Carter to get back home. They learn more about the ‘ninth ray’, a source of infinite energy and how the medallion works, but are attacked by Shang's minions, the Green Martians of Warhoon.
The attackers are fought off by Helium's ships, but the price is Dejah reluctantly agreeing to marry Sab Than. She gives Carter the medallion and tells him to return to Earth. But Carter stays and, with Sola, seeks the Tharks help in overthrowing Zodanga. However, Tarkas has been overthrown and an injured Tarkas and Carter are pitted in a coliseum against two Great White Apes. Carter kills the apes and Tarkas's usurper and becomes leader of the Tharks.
The Zodangan army double-crosses Helium and invades. The Thark army joins the battle on Helium's side, to their surprise, and they triumph. Sab Than is injured by Carter but killed by the Thern's weapon. Shang escapes.
Carter becomes Prince of Helium by marrying Dejah. On their first night, Carter decides to stay on Barsoom and throws away his medallion. Seizing this opportunity, Shang briefly reappears and sends him back to Earth.
Carter embarks on a quest to look for clues of the Therns' presence on Earth, hoping to find another medallion. After ten years, an archeological dig on the Orkney Islands makes a key find.
Back in the present, Burroughs reads that Carter has now returned to Barsoom but his body on Earth is under threat from Therns and Burroughs is to be its protector for if it's harmed then his Barsoom projection will die. Carter warns Therns may even be attempting this before his nephew has finished reading the journal.
Burroughs runs back to Carter's tomb and unlocks the door, having been told he's the key and remembering his uncle called him Ned. As he opens the door and finds it empty, a bowler-hatted Thern, who was observing Carter before his death and is now following Ned, steps forward from the dark to attack. Carter appears and kills the Thern, taking his medallion. Ned realises Carter never found his own medallion, and instead faked his own death to lure a Thern into a deadly trap. Carter confirms this, and Ned agrees to be his protector on Earth. Carter re-enters the tomb, whispers the code, and is projected back to Barsoom.