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Brothers Walter (Josh Hutcherson) and Danny (Jonah Bobo) can never seem to get along with each other, or with their older sister, Lisa (Kristin Stewart). One day, when their father sets off for work, they quarrel yet again while Lisa is in her bedroom upstairs. Danny is banished into the house's basement by older brother Walter for hitting him in the face with a baseball. There he discovers a clockwork-driven space-themed board game called "Zathura". It is a race game, and the objective is to reach a space location called Zathura. At each turn, one of its two markers moves along or back on its track, and the game issues a card (all of which are read primarily by Walter, as Danny cannot read properly) of which the effects happen immediately (similar to the clues of Jumanji). The boys start playing the game. On looking out, one of them sees that it has become night, and that the house is no longer on Earth but on a small rock floating in space. According to the instructions, the house will not return to Earth until the game is finished. During the story, the brothers must overcome their ill will toward one another to survive.
Danny and Walter try to tell Lisa, who is in bed, about what happened, but she believes that it is nighttime and refuses to believe the two. When Danny takes his next turn, they receive a card saying that Lisa is frozen in cryonic sleep, leaving the two brothers to fend for themselves. When Walter takes a turn, a toy-sized robot is brought into existence, but grows larger and becomes programmed to attack him. After being chased through the house, the robot becomes disabled falling into the basement as the house falls into the gravitational field of a star. Unexplainedly, the house stops falling into that star. When Danny takes another turn, Zorgons, which are lizard-like aliens, appear in a ship from nowhere and attack the house. Amid the chaos, Walter receives a 'Reprogram' card (which he tries to use on the Zorgons to no effect), and Danny receives a card "Rescue stranded astronaut"; an astronaut appears and must be rescued. The astronaut helps the two to get rid of the Zorgons by turning off all heat in the house, as the Zorgons' vision is thermal and therefore can only see heat signatures. The astronaut sets a couch on fire and pushes it into space; the Zorgons leave and follow it. The astronaut tells them of the dangers of Zorgons, and telling them that they travel the universe to find heat. After an argument, Danny allows the astronaut to stay to help the two through the rest of the game, much to Walter's disappointment.
Returning to the game, Walter notices Danny has illegally moved his piece forward and accuse him of cheating; he forcibly moves it back while berating Danny, resulting in two arguments one before the move and another after that. The game interprets only Walter's action as cheating and the game punishes him by getting him sucked out into space, but he is rescued by the astronaut, who has a jetpack. The incident increases the tensions between the two brothers. When Walter takes another turn, he receives a '"Shooting star, make a wish as it passes"' card, and following yet another argument instigated by the card an Danny throwing the game down in anger, Walter wishes for a football signed by Brett Favre. Having feared that Walter wished for Danny to not exist, the astronaut tells the two that he played the game with his brother many years ago, and him and his brother also despised each other. The astronaut received a "Shooting star, make a wish as it passes" card, and wished for his brother to never be born, therefore leaving him stuck in the game. This story prompts both Danny and Walter to reconcile, and the astronaut promises to protect the two from any future threats in the game.
By now, Lisa has come out of her cryonic stasis. The boys and the astronaut do not see her turning up thermostat to heat the house because she felt cold, and the resulting heat and light draw Zorgon ships back. The Zorgons shoot at the house, further damaging it, and anchor to it with grapples, and suck the game into their ship along with miscellaneous house debris, which they shovel into their ship's engine in order to use them as fuel. Lisa, now knowing what has happened, joins the trio. Danny, Walter, Lisa, and the astronaut take refuge in a small room in the upstairs of the house, at the point that safest area in the house as the Zorgons boarded the house in the basement. The astronaut heads downstairs to try to retrieve the game, but is forced to return upstairs in vain. Danny reluctantly decides to retrieve the game by heading down the basement via a dumbwaiter, which is large enough for only him (out of the four of them) to fit into, and riskily going through a boarding passage into the Zorgon ship where he frees a group of four-eyed goats to distract one of the Zorgons. He rescues the game at the last moment before it would have been shoveled into a furnace. Meanwhile, a Zorgon arrives upstairs to inspect that part of the house, and at the same time, another Zorgon spots Danny getting into the dumbwaiter. The Zorgon alerts the others and a group of them attacks Danny as he tries to head upstairs. Danny is rescued by Walter, but the two are surrounded on the stairway by Zorgons.
The robot, having revived, tries to attack the boys. Walter uses the "Reprogram" card (which he had drawn earlier) on the robot, which then attacks the Zorgons. Of the two Zorgon spaceships, one flees, and another explodes. One Zorgon survives the robot's kamikaze attack and sneaks up behind Walter and Danny as they are wondering where Lisa is. Before the Zorgon can kill them, Lisa crushes and kills it by shoving Danny's piano down on it. Walter, drawing another "Shooting star, make a wish as it passes" card, wishes that the astronaut had his brother back. A copy of Danny appears. The astronaut apologizes to the copy of Danny, who appears to be his brother. It is revealed that the astronaut and his brother are Walter and Danny from an alternate timeline which started when Walter at the first wish card wished otherwise: "I wish my brother had never been born." The astronaut's brother disintegrates into sparks which enter Danny when the two touch. The astronaut thanks Walter and tells him to take care of Danny, then touches Walter and turns into a copy of him, which smiles at him and disintegrates into sparks which enter him. Thus the two timelines merge, and the future caused by Walter wishing Danny away is erased. Lisa is alarmed to find that she had fallen for an older version of her brother, Walter.
In the last throw of the game, the Zorgons, who are now on the warpath against the humans, return with a large fleet, and start blasting the house. Danny scores a move which brings his marker to Zathura, and the Zorgons stop firing. Zathura turns out to be a black hole, which sucks up the Zorgons along with the house, Lisa, Walter and Danny. Moments later, the house is back on Earth, whose structure and furnishings are as they were before the game began and in perfect condition. As the trio's mother arrives to take them to her house, Lisa orders Walter and Danny to never speak of what happened but as they leave, Walter's bike which appeared floating in space several times drops onto the lawn.