In 1954, Godzilla, an ancient alpha predator, is lured to an island in an attempt to kill it with a nuclear bomb. In 1999, Project Monarch scientists Ishiro Serizawa and Vivienne Graham investigate a colossal skeleton unearthed in a collapsed mine in the Philippines. They find two giant spores; one dormant and one hatched that made a trail into the sea. In Japan, the Janjira Nuclear Power Plant experiences unusual seismic activity; and Supervisor Joe Brody sends his wife Sandra and a team of technicians into the reactor. A tremor breaches the reactor, leaving Sandra and her team unable to escape while the plant collapses.
Fifteen years later in 2014, Joe's son Ford, a U.S. Navy explosive ordnance disposal officer, returns from a tour of duty to his family in San Francisco but has to immediately depart for Japan after Joe is detained for trespassing in the Janjira quarantine zone. Joe persuades Ford to accompany him to their old home in the quarantine zone to retrieve vital data. They successfully retrieve the data but are discovered by soldiers and taken to a secret facility in the power plant's ruins. After several power failures, a giant winged creature emerges and escapes, destroying the facility. Joe is severely wounded and dies as he and Ford are taken by helicopter to the U.S.S. Saratoga. The incident is reported around the world as an earthquake.
Serizawa, Graham, and Ford join a U.S. Navy task force led by Admiral William Stenz to search for the creature, called "MUTO" (Massive Unidentified Terrestrial Organism). Serizawa and Graham reveal to Ford that a 1954 deep sea expedition triggered the appearance of Godzilla, nuclear tests in the 1950s were really attempts to kill Godzilla, they have been secretly studying Godzilla, the MUTO caused the Janjira meltdown, and how Godzilla and the MUTO are connected with each other. Ford reveals that Joe had monitored echolocation signals that indicated the winged MUTO was communicating with something.
The MUTO attacks a Russian submarine and drops it in Hawaii, on land. Godzilla arrives, causing a tsunami in Honolulu and briefly engages the MUTO in battle, before it flees. Meanwhile, a second, larger, wingless MUTO emerges from the other spore in Nevada and devastates Las Vegas. The scientists deduce that the second MUTO is female, the female was the one the male was communicating with, and that the two MUTOs will meet to breed in San Francisco. Over the scientists' objections, Stenz approves a plan to use nuclear warheads to lure and destroy the monsters. Ford joins a team delivering the warheads by train. The female MUTO intercepts the train and devours most of the warheads. The single remaining warhead is airlifted with Ford to San Francisco and activated after Godzilla arrives. The male MUTO steals the warhead and takes it to the female, who forms a nest around it in the Chinatown area.
While Godzilla and the MUTOs battle, a strike team, including Ford, enters the city via HALO jump to find and disarm the warhead. Unable to access the timer, the rest of the team sets the warhead on a boat for disposal at sea. The MUTOs are eventually able to get the upper hand, but Ford blows up the MUTO nest, ultimately distracting the MUTOs enough to allow Godzilla to emerge victorious in the end, killing the male MUTO by slamming him into the side of the 50 California Street building and the female by firing his atomic breath down her throat, beheading her. Godzilla then collapses on the city shore. With the rest of the team wiped out, Ford uses the last of his energy to get the boat with the warhead out to sea. He is rescued before the warhead explodes and reunites with his family at an emergency shelter the following morning. Godzilla awakens, rising from the destroyed San Francisco, and returns to sea. The media hails Godzilla as "King of the Monsters - savior of our city?"
- Ash Ketchum, Pikachu, Misty, Togepi, Brock, The Digidestined, SpongeBob SquarePants, Patrick Star, Squidward, Sandy Cheeks, Mr. Krabs, Ed Edd n' Eddy, the Mighty Morphin Power Rangers, The Masters of Evil and The Crime Empire will be guest starring in this film.
- The Masters of Evil and The Crime Empire will work for the M.U.T.Os in this film.