Caltech seismologist Dr. Lawrence Hayes and his colleague Dr. Kim Park are at Hoover Dam testing a new earthquake prediction model when a nearby and previously unknown fault ruptures, triggering a 7.1-magnitude earthquake that collapses the dam. Park sacrifices himself to save a young girl and gets swept away by the water.
Hayes discovers that the entire San Andreas Fault is shifting and will soon cause several massive earthquakes, potentially destroying cities along the fault line. He begins racing to warn the population of California, along with his students Alexi and Phoebe and reporter Serena Johnson.
When a 9.1-magnitude earthquake devastates Los Angeles and San Francisco, Ray Gaines, a chief rescue helicopter pilot of the LAFD, who is going through a divorce from his wife Emma, finds himself rescuing her from a skyscraper in Los Angeles.
Meanwhile, their daughter Blake has been visiting San Francisco with Emma's new boyfriend, Daniel; at that moment, an earthquake strikes the city. Rubble from the collapsing parking garage pins her in Daniel's car. Panicking, Daniel leaves Blake in an act of cowardice. Ben Taylor, a British engineer seeking employment at Daniel's firm, and Ben's younger brother Ollie rescue Blake, and they reach Chinatown, successfully calling her parents for help.
Ray and Emma attempt to reach San Francisco in Ray's helicopter until it suffers a gearbox failure, forcing them to make an emergency landing at a shopping mall in Bakersfield. Amid the chaos of looting, Ray steals a truck to continue the journey. The pair encounters a couple broken down on the side of the road shortly before the San Andreas Fault, which has torn a large fissure through the highway and extends for the perceivable length of the fault in either direction.
Ray and Emma exchange the truck for an aeroplane the couple owns. As Blake, Ben, and Ollie attempt to reach Nob Hill to signal the pair after finding their previous meeting point at Coit Tower engulfed in flames, Ray and Emma parachute into AT&T Park just before a 9.6-magnitude quake hits, becoming the largest recorded earthquake in history.
As the quake subsides, having destroyed much of the city, Ray and Emma commandeer a boat to reach the group, only to realise a tsunami is approaching San Francisco Bay. Alongside a handful of other survivors in small ships, the two cross the wave before it crests, barely avoiding a container ship caught up in the tsunami wave. The ship crashes into the Golden Gate Bridge's centre span, killing everyone on the bridge, including Daniel, who gets crushed by a falling shipping container.
The tsunami strikes the ruined city, capsizing a cruise ship and killing thousands more. Blake, Ben, and Ollie enter the Gate, a building whose construction Daniel had been overseeing, but are still caught by the wave. As the building begins to collapse, trapping Blake underwater, Ray dives in, rescues her, and performs CPR. Emma crashes the boat through a window and drives the five of them out of the collapsing building as Ray resuscitates Blake.
The survivors regroup at a relief camp on the other side of the bay, where the reconciled Ray and Emma talk about their future. On the remains of the Golden Gate Bridge, an American flag unfolds, giving hope that the city will recover and rebuild as rescue vehicles descend on the destroyed landscape of the San Francisco Bay Area, which now extends from San Jose to Santa Cruz, turning the San Francisco Peninsula into an island.
