Brothers Walter (Josh Hutcherson) and Danny (Jonah Bobo) can never seem to get along with each other, or with their older teen-aged sister, Lisa (Kristen Stewart). While staying at their divorced father's home while he is away at work and Lisa is asleep, the boys discover an old clockwork-driven space-themed board game called "Zathura" in the basement. The two begin to play the game, the goal to be the first to reach the final space named Zathura. During each turn, the game provides a card with instructions, but the two quickly realize the cards affect reality. They soon discover the house is floating on a small rock in outer space. Meanwhile, Lisa looks out the window, and believing it is merely dark, goes to shower for her date. When the boys try to warn Lisa about what has happened, they find she is frozen in cryonic sleep as a result of one of the cards. The brother realize that the only way to end the game and hopefully return to Earth is to reach the end space of Zathura.
As they continue to play, avoiding the dangers that the game's cards throw at them, the house comes under attack by a race of aliens called Zorgons. Another card brings aboard a stranded astronaut (Dax Shepard) who goes about eliminating the house's heat sources (during which Walter turns down the house's heating thermostat) and setting a couch on fire and pushing it outside into space to lure the Zorgons' ship away with its heat signature.
As the brothers' tension rises, Walter accuses Danny of cheating by moving a piece prematurely, but when Walter tries to correct it, the game reacts as if Walter was cheating and ejects him out of the house into the vacuum of space, but the Astronaut rescues him. On Walter's next turn, he receives a card that allows him to make a wish, and considers making a wish to make Danny go away. The Astronaut quickly warns him that he and his own brother had played the game years before, and he too had received the same card. He wished his brother away, but this caused him to be stuck in the game forever without a second player. The brothers agree to work together to finish the game quickly.
Lisa wakes from her stasis, and unaware of the current events, turns up the thermostat. This causes the Zorgons to return, anchoring their ships to the house. The four evacuate to the upper floor but realize they have left the game downstairs. Danny uses the house's dumbwaiter to sneak past the aliens and retrieve the game. Danny manages to get the game aboard one of the ships, but is caught by the Zorgons when he attempts to get back on the dumbwaiter. Walter uses a robot previously brought by an earlier turn to attack the Zorgons, and the aliens retreat. As the brothers continue to play the game, Walter receives another wish card; he uses it to bring back the Astronaut's brother, which turns out to be Danny. The Astronaut explains he is an older Walter from an alternate timeline. Danny and Walter touch their counterparts, causing them to disappear.
The Zorgons return to the house with a large fleet, intent on destroying it. Danny makes a final move to land on Zathura; in space, it is revealed that Zathura is a giant black hole that sucks up the Zorgon fleet and the house. The three children then find themselves in the house as it was before they started the game on Earth, just as their father arrives home and their mother comes to pick them up.
Tim Robins as Dad
Derek Mears as Lead Zorgon
Douglas Tait as Head Zorgon
Jeff Wolfe as Master Zorgon
Adam Wills as Captain Zorgon
Zathura got a mostly positive review.