An alien spaceship crashes near Searchlight, Nevada, outside Las Vegas. Project Moon Dust, a secret Defense Department unit led by Henry Burke (Ciarán Hinds), arrives in black helicopters. Men in Black seize the ship and search for its passengers.
Jack Bruno (Dwayne Johnson) is a former mob get-away driver who drives a cab to avoid returning to jail. One of his passengers is Dr. Alex Friedman (Carla Gugino), a failed scientist who is in Las Vegas to speak at a UFO convention at the Planet Hollywood hotel.
After resisting two thugs who seek his services for a mob boss, Bruno finds two teenagers, Sara (AnnaSophia Robb) and Seth (Alexander Ludwig), in his cab. They offer $15,000 to drive to a certain destination. Burke’s men follow the cab; Bruno believes that the government agents are more mob thugs, and evades them with his driving skills. Seth’s ability to vary his molecular density helps the group to escape.
When they arrive at an abandoned house, Bruno follows them out of concern and curiosity. The teenagers retrieve the device they were looking for within a hidden underground laboratory, but the three are attacked by a “Siphon” (Tom Woodruff, Jr.), a powerful armored alien assassin. The Siphon pursues the group until its spaceship crashes into a train and the creature is wounded. The three again escape Burke’s agents, in part due to Sara’s telepathy and telekinetics.
The teenagers explain to Bruno that they are from a dying planet 3,000 light years from Earth. Its government intends to invade Earth, despite the idea being unpopular among the majority of their race, so that their kind may survive. Seth and Sara’s parents are scientists who sought a way to save their planet without invasion but were arrested before completing their experiment. The teenagers came to retrieve the successful results, but the alien government sent the assassin to stop them. To save both worlds, they must retrieve their spaceship and return home.
Bruno brings Seth and Sara to Dr. Friedman at the UFO convention, who realizes that the teenagers are what she has been searching for and joins the group. Fellow UFOlogist and conspiracy theorist Dr. Donald Harlan (Garry Marshall) tells them that the spaceship was taken to the secret California government base Witch Mountain. Harlan and his men distract the soldiers with Bruno’s taxi while the others escape to Witch Mountain on Harlan’s RV. The group arrives at the base but are captured; Burke orders that the teenagers be prepared for vivisection, but frees the adults as no one will believe their story.
The Siphon attacks Witch Mountain and battles the soldiers, allowing Bruno and Friedman to infiltrate the base and free Seth and Sara. They launch the ship, escape through the mountain’s tunnels, and finally kill the assassin who has stowed away on the spaceship. The teenagers give Bruno and Friedman a tracking device that will allow the aliens to always find them, tearfully wish them farewell, and return to their planet.
Bruno and Friedman become successful authors of Race to Witch Mountain: A True Story. They promote their book and knowledge on the UFO convention circuit, explaining that the publicity protects them from government reprisal. As they leave a convention the alien device activates, implying that the teenagers may be returning to Earth.