Five years after the existence of giant creatures known as “Titans” was exposed to the world, Dr. Emma Russell, a paleobiologist who works for the Titan-studying organization Monarch, and her daughter Madison witness the birth of a larva dubbed Mothra. Emma calms Mothra down with the “Orca”, a device capable of emitting frequencies that can attract Titans or alter their behavior. A group of eco-terrorists, led by Alan Jonah, suddenly attack the base, slaughter everyone and kidnap Emma and Madison. Mothra flees and pupates under a waterfall.
Monarch scientists Dr. Ishirō Serizawa and Dr. Vivienne Graham approach former employee Dr. Mark Russell, Emma’s ex-husband and Madison’s father, to help track them down. Mark is reluctant at first, due to his hatred for Godzilla (whom he blames for the death of Madison’s brother Andrew), but he eventually agrees. The Monarch team follows Godzilla to Antarctica, where Jonah intends to free a three-headed Titan codenamed “Monster Zero”. Emma frees and awakens Monster Zero, which kills several Monarch members, including Dr. Graham, before battling Godzilla and escaping. The team then learn that Emma was not kidnapped by the terrorists, but is secretly working with them. Emma contacts Monarch and argues that the Titans must be awakened in order to heal the Earth from the damages that humans have caused.
From a Monarch bunker in Boston, Jonah and Emma use the Orca’s signal remotely to awaken another Titan, Rodan, in Mexico. Monarch lures Rodan into fighting the approaching Monster Zero, but Monster Zero swiftly defeats Rodan before being ambushed by Godzilla, who severs his left head. During the fight, the Navy launches a prototype missile called the “Oxygen Destroyer”, seemingly killing Godzilla. Completely unaffected, Monster Zero regrows his lost head and awakens all the other dormant Titans around the world, with Rodan submitting to his rule. Disillusioned, Madison disowns her mother.
Through mythological texts, Dr. Ilene Chen discovers that Monster Zero is Ghidorah, an ancient alien seeking to transform the Earth to his own liking. Mothra emerges from her cocoon and flies to Monarch’s Bermuda base to communicate with Godzilla, who survived the detonation and is recuperating in an ancient underwater city. Via submarine, the team locates Godzilla’s lair, where the whole area is highly radioactive. They deduce that it will take far too long for Godzilla to heal on his own and decide to detonate a nuclear warhead to speed up the process. Dr. Serizawa sacrifices himself by manually detonating the weapon, which revives Godzilla and increases his power.
Emma realizes that the destruction that Ghidorah and the other Titans will bring to the world is much worse than anything that humans could inflict, but Jonah ignores her pleas to stop. Unknown to them, Madison overhears this and steals the Orca. Arriving at Fenway Park, Madison broadcasts a frequency that calms the Titans and unwittingly attracts all of them to her location. Ghidorah lands in Boston to destroy the Orca, with Godzilla arriving with Monarch’s assistance to engage him in battle. Mark leads a team to rescue Madison and escape the city after learning that Godzilla’s radiation levels are increasing and will lead to a thermonuclear explosion. Mothra arrives to help Godzilla but is intercepted by Rodan; she defeats him, but is injured in the process.
Ghidorah overpowers Godzilla and prepares to kill him, but Mothra sacrifices herself and transfers her energy to Godzilla, rapidly healing him. Mark, Emma, and Madison are reunited and reactivate the Orca to lure Ghidorah away from Godzilla. Emma sacrifices herself to lead Ghidorah away, giving Mark and Madison time to escape. Godzilla enters a newly-empowered state, glowing red and melting everything around him. In this state, he easily defeats Ghidorah and disintegrates him completely with several nuclear pulses. After Godzilla reverts to his normal state, Rodan and the other Titans arrive and bow down to him.
During the end credits, news clippings and Monarch files show that the Titans are helping to heal the planet, a suspected second Mothra egg has been discovered, some of the Titans are converging on Skull Island, and ancient cave paintings show Godzilla battling Kong. In a post-credits scene, Jonah and his forces purchase Ghidorah’s severed left head in Mexico.