The film begins in year 2009, when there is a huge explosion on the surface of the sun. We then see Adrian Helmsley (Chiwetel Ejiofor), an American scientist, traveling to a copper mine in India to meet his friend, who discovered that Earth's temperature is increasing rapidly. He returns to Washington D.C. and submits a report to his supervisor, who immediately takes him to the president (Danny Glover). In 2010, we see the President of the United States tell other heads of state the situation and we also see billionaires all over the world buying plane tickets for untold sums of money. In 2011 the original of The Mona Lisa in the Louvre is replaced with a decoy, and is sealed away for unknown reasons.

The story jumps ahead to 2012, to Jackson Curtis (John Cusack), a divorced father who works as a limousine driver and writer, and his ex-wife, Kate Curtis (Amanda Peet), and children, Noah (Liam James) and Lily (Morgan Lily), who live with Kate's new boyfriend, Gordon (Thomas McCarthy). Jackson takes his children on a camping trip to Yellowstone, where he meets Charlie Frost (Woody Harrelson), who hosts a radio segment that addresses the Mayans' prediction.

Enormous cracks soon develop along the San Andreas Fault, California, and disruptive shaking occurs in the San Francisco Bay area, nearly knocking over a cruise ship. Despite government assurances that all is fine, Jackson grows suspicious. After hiring a private plane, he drives to Kate's home to save his family and Gordon from the impending earthquakes of the Earth's crust displacement. Jackson quickly collects his family, and Gordon pilots a plane out of the city. Los Angeles then collapses into the Pacific Ocean. When the plane runs low on fuel, they are forced to land in Wyoming. Jackson uses the moment to contact Charlie, regarding a map to ships being built in order to save humanity. They return to Yellowstone to find Charlie, only to discover that he has gone to the mountains to watch the approaching catastrophe. After getting hold of the map they discover that the ships they are searching for are in China. Jackson and his family leave just in time as Yellowstone's caldera erupts.

In order to get to China they convince a Russian billionaire, Yuri Karpov (Zlatko Buric), to allow them aboard his plane. The group eventually boards an Antonov at Las Vegas International Airport, as Las Vegas is destroyed by earthquakes and ravaged by the impeding volcanic ash cloud of Yellowstone.

While in the air, the group learns that the plane does not have enough fuel to reach China: they've passed Honolulu, Hawaii, which has been inundated in lava. As they're about to ditch the plane they discover that they are no longer above the ocean: the Earth's crust has shifted thousands of miles and they are heading towards the Himalayas. During a crash landing on a glacier they manage to escape from the plane safely by using one of the luxury vehicles in cargo as a raft, only to be abandoned by Yuri.

The group eventually find their way to the ships with the help of some locals and are smuggled aboard with the help of a Buddhist monk and a construction worker. Tsunamis begin to engulf the Indian peninsula, and a giant wave eventually reaches the ships, which turn out to be arks constructed to save the heads of state, hand-picked individuals chosen to repopulate the earth and the rich elite, who could afford to buy tickets. When the flood eventually recedes, the captains of the arks decide upon the Cape of Good Hope in South Africa as a suitable place to reestablish humanity. The movie ends with a view of the world showing the dramatically changed African continent.

• John Cusack as Jackson Curtis, a science fiction book writer who occasionally works as a limousine driver
• Amanda Peet as Kate Curtis, Jackson's ex-wife
• Liam James as Noah Curtis, Jackson and Kate's son
• Morgan Lily as Lilly Curtis, Jackson and Kate's daughter
• Thomas McCarthy as Gordon, Kate's current boyfriend and a plastic surgeon.
• Danny Glover as Thomas Wilson, the President of the United States
• Thandie Newton as Laura Wilson, the First Daughter
• Chiwetel Ejiofor as Adrian Helmsley, scientific advisor to the President
• Oliver Platt as Carl Anheuser, the President's Chief of Staff
• Woody Harrelson as Charlie Frost, a man who prophesies the end of the world and is considered crazy by others. Alex Jones has claimed Harrelson told him that Frost's character was based on him. It is more likely that this character was based upon Art Bell. Harrelson compared his character to the mythological Greek figure Cassandra, whose predictions were dismissed