Walter and Danny are two brothers who do not get along with each other or with their cantankerous teenage sister, Lisa. While their divorced father is away at work and Lisa, whom he left in charge, is napping, Danny discovers an old science fiction-themed board game called Zathura in the basement. When he starts playing, the game produces a card that details a meteor shower. After an actual meteor shower occurs in the living room, Walter and Danny realize the game is affecting reality.
The boys discover the house is floating in outer space. Lisa thinks she has overslept because of the dark sky and prepares to go out, however the next card puts her in cryonic sleep, leaving her frozen solid. Walter soon concludes they must win the game to return everything to normal. As they continue to play, Walter and Danny overcome the dangers presented by the game, including the appearance of a defective robot, passing too close to a star, and an attack on the house by a race of reptilian aliens called Zorgons. One of Danny's turns causes an astronaut to appear, who methodically eliminates the house's heat sources, as the Zorgons are attracted to heat. The astronaut lures the Zorgons' ship away by setting the boys' father's couch on fire and ejecting it from the house.
Walter demands that the astronaut leave, but Danny chooses to let him stay. Growing increasingly agitated, Walter accuses Danny of cheating of moving his piece prematurely; when he tries to move the piece back and takes his next turn, the game reacts as if Walter were cheating and ejects him from the house, but the astronaut rescues him. Danny apologizes to Walter, but he does not forgive. On Walter's next turn, he receives a card that allows him to make a wish, resulting in another heated argument between the boys. The astronaut warns Walter not to make a wish out of anger.
Fearing the worst, the astronaut is relieved to discover that Walter merely wished for an autographed football. He explains his origins, saying that he and his brother had played the game before. He received the wish card, but after an escalating fight, he wished his brother was never born. This resulted in him being stranded, as he was unable to finish the game without the second player. Upon hearing this, Danny and Walter finally put their differences aside.
Lisa awakens from her stasis and, still oblivious to the situation, turns up the heat. The Zorgons return and anchor their ships to the house. Lisa finally discovers the predicament and the quartet hide, only to realize that they left the game behind. Danny finds the game aboard one of the Zorgon ships, but is spotted. Walter uses a "Reprogram" card he drew earlier to fix the robot, who attacks the Zorgons instead, causing them to retreat.
Walter receives another wish card; he uses it to bring the astronaut's brother back into existence. The astronaut reveals he is actually an older version of Walter from an alternate timeline and commends his past self for making a better choice than he did. The astronaut and the alternate Danny merge with their counterparts as the timeline changes.
The Zorgons return to the house with a massive fleet, with the intent of destroying it. When Danny makes the winning move, it is revealed that Zathura is a black hole, which proceeds to consume the Zorgons' fleet and the house. The siblings find themselves back in the house as it was before the brothers started the game, just as their father returns home. Their bond renewed, they promise to each other and Lisa to not tell anyone about the game and their adventure.
