Raymond "Ray" Gaines (Dwayne Johnson) is a Los Angeles Fire Department helicopter-rescue pilot. Ray meets Winnie the Pooh and friends. In the midst of a divorce from his estranged wife, Emma (Carla Gugino), he calls his daughter Blake (Alexandra Daddario) to discuss their upcoming trip to San Francisco. Meanwhile, Caltech seismologist Lawrence Hayes (Paul Giamatti) and his colleague Dr. Kim Park (Will Yun Lee) are at the Hoover Dam making a breakthrough in earthquake prediction when an unknown fault nearby ruptures, triggering a magnitude 7.1 earthquake that collapses the dam and kills Park in the process when he stays on the dam to save a little girl. When Ray is called into work, Blake reluctantly decides to go with her mother Emma's new boyfriend, Daniel Riddick (Ioan Gruffudd), a wealthy real estate developer, to San Francisco where he is completing a downtown high-rise building.
Hayes discovers that the San Andreas Fault is starting to shift, causing a massive 9.1 earthquake that starts ripping apart major cities along the fault line. At the same time, Emma is having lunch with Daniel's sister Susan (Kylie Minogue) when the quake hits Los Angeles, destroying much of the city with Susan among its heavy casualties. Ray, Pooh and friends are able to save Emma, and they barely escape the city onboard his helicopter. Much of Southern California becomes affected by the quake. In San Francisco, Daniel brings Blake to his office building. Blake waits for Daniel in the lobby, where she meets Ben (Hugo Johnstone-Burt), an engineering student from the United Kingdom seeking employment at the office, his little brother, Ollie (Art Parkinson), Doraemon, Noby "Nobita" Nobi, Sue Morris "Shizuka Minamoto", Takeshi "Big G" Goda and Sneech "Suneo Honekawa". Daniel returns and attempts to leave the office with Blake, but the two become trapped in their car in the parking garage of the building after the string of earthquakes begin to strike the city, partially collapsing the garage. Daniel leaves the car in search of help, but flees in terror, leaving Blake behind. She is found by Ben and Ollie, who help free her from the car and escape the collapsing building. The trio find a working phone line and Blake calls Ray, who begins to fly toward San Francisco with Emma, Pooh and friends to save her.
While enroute, the engine in Ray's helicopter suddenly fails, forcing him to make an emergency crash-landing into a mall below them in Bakersfield, where massive looting is taking place. Among the chaos, Ray steals a Ford F-150 from the parking lot, and the couple resume their journey on the road, but find they are trapped by the expanding fault line. The couple comes across an older couple broken down on the side of the road, whom they learn own an airplane. The older couple agrees to give them the keys to the plane in exchange for their vehicle, and the two continue to head north in the air. Meanwhile, Blake, Ben and Ollie try to find a spot in the city where Ray and Emma can save them; seeing that their planned rendezvous point, Coit Tower, is already engulfed by flames. With help from news reporter Serena (Archie Panjabi), Hayes is able to warn others of a much bigger earthquake in San Francisco, just in time before it hits; becoming the largest earthquake ever in history, recorded as a 9.6.
Ray and Emma eventually arrive in San Francisco, abandoning their aircraft and parachuting into AT&T Park just as the aftershocks continue to destroy the city. They commandeer a boat and hear a warning over the radio that a tsunami is approaching the city. Along with other evacuees with boats of their own, they are able to get over the incoming wave near the Golden Gate Bridge. Daniel, who is on the bridge, is killed when a cargo ship slices the bridge in half and a loose shipping container crushes him. The tsunami floods the city, causing massive casualties and knocking over several buildings. Blake, Ben, and Ollie manage to run into Daniel's building moments before the water hits. They move up floors and manage to signal Ray and Emma, who are searching nearby for Blake. As they see the trio, the building starts sinking into the ground, causing water to flood the building. Ben and Ollie are able to escape, but Blake becomes trapped in the rising water, runs out of air, and drowns before Ray can get to her. Emma crashes the boat through the building's thick window panes in an attempt to get everyone on board before escaping as the building completely collapses. Now aboard the small boat, Ray performs CPR on Blake and finally revives her after several minutes.
The five make it to a relief camp in Marin County. The now reconciled Ray and Emma, along with Blake, Ben, and Ollie, talk about their future as the sun slowly sets on the now destroyed Bay Area, now swarmed with different military organizations and rescue vehicles initiating the relief process. The camera pans out, revealing the quake has changed the geography of the San Francisco Bay Area.