The film opens with the girl, Natalie (Morgan Griffin), driving through the cliff of San Fernando Valley, 16 miles (25.75 kms) north of Los Angeles, when suddenly the rock slides onto the car, causing it to fall then hang into the edge of cliff. Moments later, Los Angeles Fire Department helicopter-pilot Chief Raymond "Ray" Gaines (Dwayne Johnson) and his other colleagues comes to rescue the girl trapped in the car. Ray safely rescues the girl moments before the car falls into the cliff.

In CALTECH, Dr. Kim Park (Will Yun Lee) receives a data of minor earthquakes in Falco, Nevada and shows it to his collegue and seismologist Lawrence Hayes (Paul Giamatti). The minor quakes measure 2.0 to 2.6. Hayes is curious of why such a minor quakes can produce even there are no faults in Nevada. Hayes and Park decide to go to Nevada to test the theory.

While Ray is calling for his daughter, Blake (Alexandra Daddario), for the upcoming trip to San Francisco, he receives a divorce papers. Recently, he is divorced from his estranged wife Emma (Carla Gugino) and she is now with his new boyfriend Daniel Riddick (Ioan Gruffudd).

Meanwhile, at the Hoover Dam, along with Hayes, Park is now testing a magnetic pulse of quake. Suddenly, his device detects a sudden spike pulse then a stronger earthquake triggers. It measures 7.0 that ever recorded. As the dam starting to break, Park struggles to escape while Hayes tells the people, still on the dam, to get out of it. Park has now exits the dam facility, however when he sees the girl - staying beside the dam while crying - he carries her out. After rescued the girl, Park is being impaled by a rod in his right foot. The dam completely crumbles and Park is killed. The disaster leading to the flooding in most town and the earthquake was the strongest and destructive ever recorded in Nevada's history.

Back to California, Ray arrives at his family house for planning what to do for the trip. After that, Ray is back to work for another mission: rescue the disaster victims in Nevada. Daniel and Blake head to San Francisco for the meeting. While Daniel is having a meeting, Blake meets an English guy named Ben Taylor (Hugo Johnstone-Burt) - having for an interview - and her brother, Ollie (Art Parkinson).

In CALTECH, the reporter, Serena (Archie Panjabi) arrived and wants to interview with Hayes about what happen in Nevada. Hayes states that they didn't know that there is any fault line in there. He learns that they can predict an earthquake just like they did along with Park. One of his colleague interrupts Hayes and he presents him the data showing the pulse rates where detected on the entire San Andreas fault. The pulse rates were higher than Nevada. Hayes then explains to them on why the earthquake triggered in Nevada even there are no fault line: his theory is to draw a fault line near Nevada and it connects to the end of the fault boundary. Hayes predicts that the whole San Andreas might go off.

In Los Angeles, Emma is having a lunch with Daniel's sister, Susan, in a higher rise restaurant. After some conversation with Susan, Emma answers a call from Ray, in the helicopter en route for maintenance. Ray apologizes Emma for what he done on the other day. Their phone conversation is interrupted by the strong earthquake. Emma tells to Ray that they're having an earthquake and he also notice that the freeway is crumbling in the process. Ray instructs Emma to get to the roof for rescue. According to the CALTECH, the first major earthquake peaked at 8.5 and later 9.1. Not only in Los Angeles, but the whole California and the quake is heading to San Francisco where Blake and Daniel are there.

While the ensuing destructive earthquake, the people inside the building panicking in terror, others are being injured. Emma told Susan to get to the roof together, but she goes to the exit, only she killed in an crumbling floor. Emma made it to the roof, but only the floor and the surrounding structures crumbling in the process. Emma manage to recover and emerges from the rubble. Finally, Ray rescues Emma and barely escapes as the surrounding structures collapse. The whole city is now complete devastation.

Meanwhile in San Francisco, after Ben having an interview, Blake borrows Ben's book just to write her number in it to call him. As they drive inside the parking lot, the earthquake hits. They manages to escape but the floor collapses ahead and they become trapped. The debris crushes the driver, making the driver's seat to stuck Blake's leg. Daniel leaves her for help. As Daniel calls for help, the debris falls near to him. Because of this, he flees in terror instead of saving her.

Ben and Ollie are struggling to save her as the debris above her continues to press the roof. By using the screw jack to lift the debris out, Blake is still stuck but at least the driver's seat pushes away a bit. When Ben pops the tires, finally they rescued her. The trio get out of the building as the aftershock continues. Blake becomes betrayed when Daniel leaves her in danger. The trio decides to go to the electronic store in order her to contact with his family.

Blake, Ben and Ollie goes to the electronic store. Blake found the phone and she calls her parents that she's okay. Also, she tells them that Daniel left him. This makes Emma betrayal and left an intimidating message to Daniel's voicemail. Ray advises Blake that they will need to get out immediately and they will go to Coit Tower as rendezvous. Ray and Emma quickly heads to San Francisco to save her.

Meanwhile, Daniel is walking through the crowd in the street when suddenly a strong earthquake hits again. The structure aheads the crowd collapses. In order to save himself, Daniel steals the safe spot of one of its victims. The victim is being flied away by the strong dust wind.

When Ray and Emma are en route to the city, the helicopter's engine fails, forcing them to make a crash landing into the superstore in Bakersfield. As they try to steal the vehicle, which is already stolen, the perpetrator aims the gun to him but he manage to subdue the perpetrator and then they drive away.

With the help of Serena, Hayes is able to warn the others, through the news coverage, of a much bigger earthquake in San Francisco. He tells the people of San Francisco to get out now, and their lives depends on it.

After they obtaining the vehicle, they drive out when they see an old couple warns them to stop their vehicle - it is the now-opened San Andreas fault that rendering the road becomes impassable. They drive it back to the old couple who happen to own an airplane. In exchange for their stolen vehicle, Ray and Emma manage to fly their plane to San Francisco. While on the plane, Ray recaps about what happen with their daughter, Mallory, who died in a rafting accident. Ray regrets because he did not save his daughter. That's why Emma stays harder with Blake and that's the reason of Emma and Ray getting divorce. Then they fly to San Francisco

Blake, Ben and Ollie, walking through the streets of crowd, head to Coit Tower for their meeting place, but it is already engulfed in flames. So, they change the plan by going to the highest ground which is Nob Hill in order to signal her family.

Ray and Emma make it to San Francisco but they cannot land the plane because the airport has a lot of cracks and scattered planes. Ray has no choice but they will sky dive to the stadium - still standing - leaving the plane to be crash into the Pacific Ocean as long as it runs out the fuel.

Meanwhile, Blake, Ben and Ollie are walking through the deserted street when the strong earthquake hits. The earthquake measures 9.6, the largest recorded in the history. Blake and Ollie quickly get into the side of the street but Ben goes into the opposite side. The glass shard, coming from the building, pricks Ben's leg. The remaining still standing structures destroy, ground ruptures, suspension bridge crumbles, etc. At the same time, Ray manages to tell other people to get the side of the stadium safely and the higher beams nearly crashes them - but all of them are safe.

After the earthquake, Blake carefully removes the glass shard from his leg and then they move to the highest ground. Ray and Emma drive in the boat to the city where they see a Coit Tower is on fire. He knows that she's gone somewhere else. They notice that the water recedes quickly, which means that the tsunami is about to hit the city. As the trio receives the tsunami warning from the radio, it is too late for them to head to the highest ground. So, the trio quickly heads to the Daniel's unfinished building.

Ray and Emma, in the boat, and the other boats manage to drive into the giant tidal wave. They almost made it through but they almost hit to the cargo ship, that carry by tidal wave. Daniel, is still on the Golden Gate Bridge, is being crushed by loose ship container, killing him. The cargo ship slices the Golden Gate Bridge in half and the tidal wave continues to hit the city. Sadly, most of the people, still on the ground, didn't made it.

The trio is in now in the building when the tidal wave hits. Ray and Emma drives through the devastated town to find Blake. Blake and Ollie sees her parents riding in the boat but they are unknown to them. Ollie then uses the laser pointer - that he obtained from the electronics store - to attract her parents. Now the parents sees them inside the building, but before can save them, the building starts to sink into the ground. Blake is separated from the two brothers as they made it up to the floor. Blake is now trapped inside as the water continues to rise up. Ray manage to rescue his daughter, only the exits are jammed. Blake then apparently dies from drowning and Ray struggles to get her out. Ray then do a rescucitate Blake, but as the building is going to collapse, Emma drives through the window and they quickly get it out as the building finally collapses completely.

Once outside, after Ray tried to revive Blake, she's now back to her life and finally reunites with her family. Later, the five make it to a relief in Marin County. The family along with Ben and Ollie watch the sunset, on the destroyed and radically altered geography of the San Francisco Bay Area, and they talk about the future. They also see an American flag is wave to the now-destroyed Golden Gate Bridge.