In 1954, Godzilla, a prehistoric alpha predator, is lured to Bikini Atoll in an attempt to kill him with a nuclear bomb. In 1999, Monarch scientists Ishiro Serizawa and Vivienne Graham investigate the skeleton of a monster similar to Godzilla in a cavern unearthed by a collapsed uranium mine in the Philippines. They find two giant spores, one dormant and one hatched, along with a trail leading to the sea. In Japan, the Janjira Nuclear Power Plant experiences unusual seismic activity. Supervisor Joe Brody sends his wife Sandra to lead a team of technicians into the reactor. A tremor breaches the reactor, forcing Joe to close the reactor door before Sandra and her team can escape while the plant collapses.

Fifteen years later, Joe and Sandra's son Ford, a U.S. Navy EOD officer, returns from a tour of duty to his wife, Elle, and son Sam in San Francisco. He departs for Japan after Joe is detained for trespassing in Janjira's quarantine zone. Joe is determined to find out the cause of the meltdown and persuades Ford to accompany him to retrieve vital data from their old home. They learn that the zone is uncontaminated and retrieve the data, but they are discovered and taken to a facility in the plant's ruins. The facility harbors a massive chrysalis that had been feeding off the plant's reactors for 15 years and emitting intense electromagnetic pulses over time. A giant winged insect-like creature emerges from the chrysalis and escapes, destroying the facility. Joe is severely injured and later dies. The incident is reported publicly as an earthquake.

Serizawa and Graham join a U.S. Navy task force led by Admiral William Stenz to search for the creature, dubbed a "MUTO" (Massive Unidentified Terrestrial Organism). Serizawa and Graham reveal to Ford that a 1954 deep-sea expedition awakened Godzilla. Nuclear tests in the 1950s were attempts to kill him; when this did not work, Project Monarch was established to study Godzilla and similar monsters secretly. They explain that the MUTO caused the Janjira meltdown. Ford reveals Joe had monitored echolocation signals indicating the MUTO was communicating with something, presumably Godzilla.

The MUTO attacks a Russian submarine and drops it in O'ahu to eat its nuclear material. Godzilla arrives, causing a tsunami in Honolulu, and briefly engages the MUTO in battle until it flees. Serizawa deduces Godzilla was only listening as the MUTO was communicating with something else, prompting the military to investigate the other spore stored in the Yucca Mountain nuclear waste repository in Nevada. A second, bigger, wingless MUTO has emerged and attacks Las Vegas. The scientists deduced that it was female and was what the male was communicating with, their signals being a mating call.

Over the scientists' objections, Stenz approves a plan of using nuclear warheads to lure all three monsters out into the open ocean and destroy them. Returning to the U.S., Ford joins the team delivering the warheads by train, but the female MUTO intercepts them and devours most of the warheads. The remaining warhead is airlifted with Ford to San Francisco, where the monsters are converging, and activated after Godzilla appears at the Golden Gate Bridge. The male MUTO snatches the warhead and takes it to the female, who forms a nest around it in the Chinatown area.

While Godzilla and the MUTOs battle, Ford and a strike team enter the city via HALO jump to find and disarm the warhead before it detonates. Unable to access the timer, the team gets the warhead onto a boat for disposal at sea while Ford destroys the nest. Godzilla defeats the MUTOs and collapses from exhaustion. Ford gets the boat out to the open sea, is rescued before the warhead explodes, and reunites with his family at an emergency shelter the following morning. Godzilla reawakens and returns to the sea, while the media dubs him the "King of the Monsters".