The film opens on Stewart Graff (Charleton Heston) jogging underneath the Hollywood sign. Back home, as he finishes his workout on a resistance machine, his shrewd wife Remy Royce-Graff (Ava Gardner) starts her morning by picking a fight with him. At the peak of their argument, Stewart says to Remy, "You'd hardly call this a marriage wouldn't you?" After he's showered and preparing to leave, Stewart finds Remy unconscious with a bottle of pills nearby. Accustomed to her periodic suicide attempts, Stewart prepares to induce vomiting when a violent tremor shakes the bedroom. Remy bolts out of bed, revealing that she was faking.
At the Mulholland Dam, two workers begin a routine inspection of the structure in response to the tremor. One of them is drowned in an elevator shaft which has filled with water after the quake.
In downtown Los Angeles, Sgt. Lou Slade (George Kennedy) and his partner Emilio Chavez (Pedro Armendáriz, Jr.) are in pursuit of a suspect. They chase him out of their jurisdiction, finally crashing into the hedges at Zsa Zsa Gabor's house. After a Beverly Hills Sheriff yells at Lou for ruining Gabor's hedges, the angry Lou punches him out. When reprimanded, Lou explains to his supervisor that the suspect had stolen the car, gotten stoned, and then driven over a 6-year old Mexican girl without stopping. To his disgust, he receives a temporary suspension from his unfeeling superior.
On his way to work, Stewart visits Denise Marshall (Geneviève Bujold), an actress who is the widow of one of his friends and co-workers. He drops off an autographed football for her son and helps Denise run her lines for a scene she is shooting later that day.
A junior staffer, Walter Russell (Kip Niven), at the California Seismological Institute has calculated that Los Angeles will suffer a major earthquake in the next day or two. He frantically tries to reach his superior, Dr. Frank Adams (Bob Cunningham), who is busy placing seismic sensors in the field. Another tremor hits as Adams and his assistant are working in a deep trench and they are buried alive. The scientists at the center argue about whether or not to go public with their prediction of a major quake. The acting supervisor, Dr. Willis Stockle (Barry Sullivan), insists that if they are wrong their funding will be jeopardized. He also argues that the panic such a warning would cause could be worse than the earthquake itself. They agree on a compromise to alert the National Guard and police so that they can at least mobilize to help deal with the fallout.
While checking out at a grocery store, a poor young woman named Rosa Amici (Victoria Principal) realizes she does not have enough money to pay for all her items. Jody Joad (Marjoe Gortner), the seemingly kind store manager, insists that she keep the items and make up the deficit the next time she shops. Later, when he hears that the National Guard reserves are being called up on the radio, Jody leaves the store in the middle of his shift, revealing himself to be part of the reserve army. He goes to his run-down boarding house and changes into his NCO uniform, enduring the abuse and harassment of his bullying housemates who accuse him of being homosexual because he's got pictures of bodybuilders on his wall.
Blowing off steam at a bar, Lou orders a double bourbon and ignores all the illegal activity he sees. A drunk (Walter Matthau) periodically wakes up to toast random people like 'Bobby Riggs'. Daredevil motorcyclist Miles Quade (Richard Roundtree) arrives with his partner Sal Amici (Gabriel Dell) and his sister Rosa. A pool shark collects $50 that Miles owes him, leaving him short for the propane tank he needs to do a stunt for a talent scout. Miles convinces Lou to loan him the money by having Rosa reveal a tight-fitting t-shirt he's marketing with his name on it.
The tremor cancelled Denise's shoot; so, she heads to Stewart's office, pretending to meet with a friend. When she runs into him, he is headed out for a drink. They go back to Denise's house for the drink and end up making love. He promises to come back later that night and invites her to spend the summer with him in Oregon, where he will be overseeing a project. Back at the office, his boss Sam Royce offers to hand over the company presidency to Stewart. He asks for some time to consider the idea. Stewart calls Denise and breaks off their plans for later that night. He goes to Sam's office to accept his offer but is stunned to see Remy there. He assumes she has convinced her father, Sam (Lorne Greene), to offer the promotion to Stewart in order to save their marriage. He storms out and she follows him, accusing him of cheating with Denise. He explains that he never had until that day. When they get outside the building, the main earthquake begins, rupturing the San Andreas Fault, and causing thousands of buildings to collapse and causing hundreds of thousands of people to die while shaking Southern California for nearly six to nine minutes. The earthquake is measured 9.9 on the richter scale at the Seismological Institute.
When the earthquake subsides, Sam and most of his employees are trapped on the upper floors of their skyscraper, as the elevators have crashed to the ground. They descend most of the way by the stairs, but the earthquake has sheared off a portion of the building, leaving an impasse of about two stories. Sam rigs a fire hose to a chair and lowers his staff down one at a time. When everyone is safe, he suffers a heart attack, and Stewart climbs up to lower him down in the chair.
Meanwhile, Denise's son was caught on a bridge over a freeway causeway when the quake struck. She spies him unconscious on the concrete and climbs down to save him. Unable to climb back out with her son, she hails Miles and Sal who are passing by in their truck. After saving Denise and her son, they drive in search of help, coming across Lou who is organizing rescue efforts in the street. Lou commandeers their truck to use it as an ambulance.
After nibbling on a donut in a ruined diner, Rosa has been arrested by the National Guard for looting. Jody, now a sergeant, picks her out of a group of prisoners. Recognizing him from the grocery store, Rosa assumes he is going to let her go, but he claims that the streets are too unsafe for her to go anywhere and he orders her to stay inside a secluded store. Another group of troops arrive with Jody's housemates as prisoners. Jody executes them in an act of revenge for all the long time bullying he endured from them, terrifying Rosa and his subordinates as they now see his dark psychopathic side.
Once Stewart gets everyone from his office safely to a shopping center named Wilson Plaza, which has been converted into a triage center, he goes off in search of Denise and her son. He ends up driving Lou around in search of survivors and they come across Jody and his regiment. Jody threatens to fire on them if they come any closer and Rosa emerges when she sees Lou, begging for his help. Lou and Stewart pretend to comply with Jody by driving off while Sgt. Joad's scared men look for an officer to have him face a court martial and detainment. But Lou sneaks back and gets the jump on Jody, who's enraged at Rosa for betraying and rejecting him and tries to rape her. Lou shoots Jody dead in self-defense when Jody tries to kill him with his rifle and rescues Rosa.
As they drive away, they hear that another aftershock has threatened Wilson Plaza. After a quick survey of the building, Stewart realizes there are survivors trapped in an underground garage. He and Lou crawl into the sewer and through some rubble with a jackhammer, which they use to drill through to the garage. Stewart is overjoyed to find Denise, who is one of the people trapped inside. As he hugs her, he sees his wife standing just behind her.
During the rescue, the Mulholland Dam finally gives way, sending water down the sewers. Lou and Denise make it up the ladder to safety, but as Remy climbs out, a man steps on her hand. She falls back into the water which is sweeping people away. Stewart looks up at Denise, but he cannot bring himself to abandon his wife to her death. He sacrifices himself when he swims after her and both of them are swept away and presumably drown. Denise walks away from the manhole in shock and grief. Lou is holding Rosa when a doctor walks up to him and says, "This used to be a helluva town, officer." Lou mumbles, "Yeah" as he tries not to cry. The camera pans back to reveal a completely destroyed Los Angeles.