In New York City, 1881, a man eludes another in the crowded streets. He appears anxious, and eventually enters a building. Inside he pays extra to send a telegram express. A young man receives the telegram -- his uncle is urging him to hurry and save him. The young man travels to the uncle's large estate where a lawyer explains the uncle, John Carter, died suddenly and left everything to the young man. He passes the young man, Edgar Rice Burroughs (Daryl Sabara), an old diary.
After the lawyer leaves the young man begins to read. The story begins in Arizona, after the Civil War. John Carter (Taylor Kitsch), a decorated former captain in the Confederate Army, is prospecting for gold. The locals don't seem to like him. Colonel Powell (Bryan Cranston) of the cavalry tries to press Carter into service to fight the Apache. Carter refuses to cooperate, and after several failed escape attempts, he tricks a cell guard into helping him escape Fort Grant on a stolen horse. Powell and the rest of the cavalry give chase but are forced to halt when they see that Carter has met up with a mounted Apache war band. Both sides are armed and wary, and a language barrier increases the tension. Soon a gunfight breaks out. Carter takes the chance to run off, but Colonel Powell is shot, and Carter returns to retrieve the injured man.
The two escape into a box canyon and find a small cave. The Apache approach but quickly withdraw when they see a spider-like figure carved into the rock near the cave. Confused, Carter returns to where the Apache had been standing, and notices the spider symbol on the rock face. Leaving Powell near the opening, he goes deeper into the cave to investigate. There Carter finds a chamber with strange markings. Entranced, he misses the stranger who appears behind him, and Powell is almost too late to shout a warning. The stranger is a bald man in a shining robe with a knife that seemed to have manifested out of thin air. The two fight, Carter kills the other and notices that the bald man had retrieved a blue-glowing medallion. Picking it up, Carter repeats the words he heard the other say, and suddenly he awakes in a strange desert.
Carter tries to walk but stumbles and appears to float. He spends several minutes learning how to walk in in this strange new environment. (The gravity is much lower than what he's accustomed to, but he doesn't know that.) He makes his way to the nearby tor and finds a nest of eggs hatching green six-limbed infants. Disturbed, he is about to leave when he notices a group of green creatures approaching. They are mounted on large beasts and armed with firearms, and when they see Carter they open fire until one of them tells the others to stop. This tall green alien with 4 arms lays down his sword and rifle and greets Carter. As with the Apaches, there's a language barrier but the two manage to give their names. The green man is Tars Tarkas (Willem Dafoe), the Jeddak, or leader, of his tribe. Tarkas knows Carter is not a local, and asks him to jump again. Carter takes the chance to jump towards Tarkas' weapons, but before he can fight he is overpowered.
Again Tarkas waves off the rest of his group, telling them to spare Carter. They collect the hatchlings, killing those who seem too weak, and take Carter to their home in the ruins of an ancient city. By this time Carter is horrified and out of his depth, he wants to go home and knows the medallion is likely the only way. Unfortunately, Tarkas has recovered the medallion and wears it. In the city other Tharks treat Carter roughly. They do not recognize what type of being he is and his lack of language comprehension labels him something akin to an animal or baby in their eyes. Thus, he is thrown in with the babies. As is Thark custom, the babies are released to the mob and whoever manages to catch one will be the parent of the hatchling. Carter is given to Sola (Samantha Morton), a female who the other Tharks seem to view with contempt -- particularly another female called Sarkoja (Polly Walker). When Carter had been cleaned and put inside a pit to rest with the other babies, she pours a liquid into his mouth. Afterward, he is able to speak and understand the local language.
Somewhere further away, a battle between humanoids is happening. They fight on airships, one side blue and the other side red. On a red ship, three bald figures appear and approach General Sab Than (Dominic West). They give him a blue mesh device that gives him the ability to shoot bolts of energy, but when he tries to shoot the three figures he is instead blasted backwards. The three figures laugh. They are Therns, representatives of the Goddess, and she has chosen to side with Prince Sab Than of Zodanga in this conflict. The Thern leader, Matai Shang (Mark Strong), gestures for him to test his holy new powers. The general sends bolts of energy to the enemy ships and wins the combat.
In the royal palace of Helium, Dejah Thoris (Lynn Collins) is practicing a speech. Her father Tardos Mors (Ciarán Hinds), the Jeddak, arrives arguing with an entourage. Dejah demonstrates a machine that generates a weak blue ray -- something she calls the ninth ray, which she claims is the source of their enemy Zodaga's new power. As the entourage discuss the possibilities, one of them discreetly zaps the device, making it fail. Tardos understands that this power could help level the battlefield, but they have no time to further their research into this mysterious blue ray. He dismisses the group and tells Dejah she has to marry Sab Than to end the conflict. Dejah is devastated; she knows that the wedding is unlikely to stop Zodagan expansion, and that once married she would no longer be able to continue her research.
Back in Tharkville Carter now has a guardian, Woola, a massive, wide-mouthed, low-to-the-ground creature that is very quick and insists on following Carter like a dog, no matter how high or how far he jumps. Carter is disgruntled, as he is trying to find Tars Tarkas to retrieve the medallion, but Woola is able to catch up with him and make enough noise to thwart Carter's plans. Carter ends up jumping into a Thark party, and Woola bursts in and loudly disrupts the gathering. The angry Tharks beat Woola and his owner, Sola. Enraged, Carter jumps in to stop the beating, unintentionally killing a Thark as a result and proving his ability to jump long distances. The Tharks see Carter as a new weapon but are angry at Sola for allowing him to escape. They brand her in front of Carter, who watches in horror as the Tharks warn her that her next offense will lead to death because she has transgressed so many times that she has no room on her skin for more brands.
The Tharks take cover when a sentry warns of flying craft. Three flying battleships appear in the sky, two chasing one. They close in for boarding parties and hand to hand combat. Tarkas watches with a telescope and explains the war to Carter: the Zodangans are fighting the Heliumites. On the ship Dejah Thoris attempts to escape, then falls and hangs on several hundred feet up. Carter sees she is "human" and jumps to her rescue. With his ability to jump long distances he manages to rescue the girl and starts to defend her, only for her to prove her own fighting ability. Still, Carter is able to turn the tide of the battle, but the blue Helium craft crashes.
After this spectacle Tars Tarkas makes Carter his "right arm," bestowing the name Dotar Sojat, and gives him Dejah Thoris as a prize. Tars Tarkas's rival Tal Hajus (Thomas Haden Church), a warrior with a broken tusk, looks on in angry disapproval. Carter is reminded of Powell and refuses the position, but Tarkas says that if Carter rejects the offer Tarkas would be unable to spare Dejah's life. Carter reluctantly agrees, and soon finds himself fending off everyone's inquires about his ability. Dejah wants to learn how to jump as Carter can, but figures that the ability is likely related to Carter's different bone density and thus it would not be a skill she or anyone else could learn. Tarkas knows that she is trying to gain a new weapon for Helium and warns Carter against her. Carter just wants to go home. He tries describing his home to Dejah but she thinks him either insane or a liar because he describes an environment that hasn't existed here for thousands of years. Seeing his seriousness, she guesses he is a Thern, leading them to a discussion of astronomy and finally the realization that Carter is from Earth, which she calls Jasoom, but he is currently on Mars -- Barsoom.
If there is indeed a way of traveling between the worlds the Therns will likely know the answer. Although Sola tries to stop them, Carter and Dejah Thoris enter a cave that is supposed to be a temple of the Goddess and her followers the Therns. Dejah reads some ancient markings, but before they can proceed the three are arrested by the Tharks for going into the temple. Tarkas helps them all escape, at great personal risk, and Carter guesses Sola is his daughter. Considering that Thark custom is to hatch their young in isolation and rear them anonymously, there had to have been plenty of law breaking involved.
Sola, Cater, and Dejah Thoris journey to the river Isis to solve the temple mystery, taking the medallion. Along the way Sola warns Carter that Dejah Thoris is leading them astray. Confronted, she admits they were headed for Helium, and a furious Carter makes to abandon her as he realizes she may have been manipulating him to turn him into her new weapon. He ignores Dejah's pleas until she finally admits she did have a personal interest in the battle for she is the Helium princess, likely to be married off to the Zodangan prince and potentially killed. Carter convinces her that he needs time, and that they should go to Isis first. The river is a path for pilgrims; those who have sinned or have lived too long follow the river to end their lives and find paradise. Sola, seeing what seem to be Tharks sailing away and bodies on the ground, almost joins them until Carter stops her.
Up the winding river they find an inverted stone pyramid. Carter and Dejah Thoris enter and glowing blue graphics show the solar system. Dejah Thoris realizes the blue light is not supernatural but generated by machines -- it's the ninth ray, the same blue ray she had been researching and that the enemy had been using as a weapon. They also realize that Carter's entry into Mars likely had been due to telegraphing a copy of himself from Earth to Mars.
Outside, an army of Tharks approach, directed by Matai Shang. He is curious about the stranger that is getting himself involved with the wars, and intends to test his ability. Carter and the two women mount up and scramble. As the hordes approach, Carter tells the others to flee (over Dejah Thoris's objections); he returns to fight the rampaging army with only his pet, Woola. Killing many, he recalls the devastation of war and finding his dead wife and child in a burned farmhouse. Carter is eventually overcome. Just then a Helium battle cruiser arrives to end the fight. Tardos Mors and Sab Than disembark. Sab Than offers his sword to Dejah Thoris as a sign of trust and asks her to marry him. Dejah Thoris almost kills him anyway, but stops herself and instead makes them take the wounded Carter to Zodanga to be healed.
Carter awakes in a guarded room. At first he thinks he is in Helium but the red clothed guards laugh and tells him he is in Zodaga. As he muses on being in enemy territory, a man dressed in blue appears. He is Kantos Kan (James Purefoy) and he issues orders about putting Carter under higher security. Once close enough, he whispers to Carter to take him hostage, but Carter is too confused, and an exasperated Kantos pretends to be held hostage as he leads Carter away from the guards.
The two jump to a nearby tower. Inside, Dejah Thoris is dressed in wedding finery. After thanking Kantos for bringing Carter to her she dismisses everyone in the room. Again she asks Carter again to fight on her side. He refuses again, and finally she sees the marriage ring on his finger. Understanding that his heart belonged to another but now knowing that the other woman is dead, Dejah Thoris tells him the magic words that will transport him back to earth. Outside, Zodagan guards demand entry, but when the door opens Carter has vanished. Dejah Thoris and the others leave, but the Matron of Chamber (Cate Fowler) returns to the room and finds Carter in a ceiling recess. She uses a blue ray to immobilize him then transforms into Matai Shang, leader of the Therns. He forces Carter to come with him and explains how the Therns are managing the end of Mars. To prove their ability, Matai Shang changes into a Zodagan officer (Darwin Shaw) as he leads Carter outside, then into an elderly woman (Eileen Page) as they watch Dejah Thoris being paraded down a street. Almost lightly, Matai Shang tells Carter that after the marriage Dejah Thoris and anyone else who knows about the blue ray will be killed.
Suddenly Carter's pet Woola arrives in a flurry, and he manages to escape on a flying single seater. He crash lands ouside of town, close to Sola. Knowing he is unable to challenge the Zodagan military or the Therns by himself, he decides to return to Tharkville and ask for their help. Carter and Sola arrive safely but the Tharks throw Carter in jail, where he finds an imprisoned Tars Tarkas, also in chains. Tarkas tells Carter that he had been overthrown by one-tusked Tal Hajus (Thomas Haden Church). Tarkas is furious when he learns that Carter brought Sola back, and would have killed him were not for the fact that he had been beaten and drastically weakened. The prisoners are eventually taken to a large coliseum and made to fight giant white apes. Sola causes a distraction in the stands and Carter manages to kill the two beasts. As the Tharks cheer for him, he challenges Tal Hajus for the role of Jeddak. Carter quickly beheads him. Now leader of the Tharks, he had an army willing to fight for him.
He leads them back to Zodanga to stop the wedding. On arrival they find the city empty -- everyone has gone to Helium. An unimpressed Tars Tarkas smacks Carter on the head, since there is no way they can make it to the wedding in time. Carter points to the airships but the Tharks refuse, so he takes off by himself in a single-seater. Zodangan guards spot him as he approaches but as he's flying a Zondangan aircraft, they assume he's part of their plan and let him pass. As the wedding ceremony is starting Carter crashes in. Dejah Thoris is thrilled to see him but it is too late as the signal had been cast. Zodangans begin attacking the Heliumites, and once again Matai Shang and his blue ray seem unstoppable. Suddenly a huge cruiser crashes in too, the Tharks have arrived to follow their leader. They join the Heliumite army and fight off the Zodangans. Matai Shang manages to escape but Carter recovers the medallion.
With the immediate threat of Zodanga gone and now knowing where his heart is, Carter takes his wedding wing and asks Dejah to marry him. She agrees and both Helium and Thark rejoice. That night Carter is restless and steps out of the room. He tosses the medallion far away. As he passes by a guard, the guard reaches out and grabs him, morphing into Matai Shang right before Carter is sent back to the Arizona cave. Carter wakens dusty and bearded; the Colonel is but a skeleton.
The Carter narrative continues, he realizes there must be Therns on earth and spends the next 10 years looking for another medallion. He appears to find something in the Orkneys. He prepares a crypt on his estate so he can return to Mars and leave his body safe on earth. Nephew Edgar is to be entrusted with keeping him safe because it is likely that the Therns are going to attack his body -- perhaps right at the moment when Edgar is reading the journal. Horrified, Edgar runs to check the crypt, not knowing he is being followed. After a few tense seconds he figures out the password to enter and opens the door, but the crypt is empty. A Thern appears and is about to move forward, but is shot dead. Edgar turns around to see Carter outside holding a gun. Carter explains he took a drug that made it appear that he was dead, and Edgar realizes he was simply bait to draw out a Thern and enable Carter to obtain the medallion he needs to go back to Dejah Thoris. Carter corrects him, saying that Edgar is indeed going to play a very important role: the protection of Carter's body as he returns to his true home. Taking the medallion from the dead Thern, Carter goes into the crypt, lies down and recites the phrase to return to... Barsoom!