Dr. Emma Russell, portrayed by Vera Farmiga, works as a paleobiologist for the Crypto-zoological organization Monarch, which focuses on discovering and researching colossal beings known as "Titans." Together with her daughter, Madison (Millie Bobby Brown), they witness the emergence of a giant larva named Mothra within a Monarch facility cleverly disguised as a Mayan Pyramid. Using a revolutionary device called the "Orca," capable of projecting frequencies that can influence Titan behavior, Emma successfully soothes Mothra. However, chaos ensues when a group of ecological terrorists led by Charles Dance's character, Alan Jonah, launches an attack on the base, abducting both Emma and Madison.
As Mothra escapes and pupates beneath a waterfall, Monarch scientists, including Ken Watanabe as Dr. Ishiro Serizawa and Sally Hawkins as Dr. Vivienne Graham, approach Emma's ex-husband, Kyle Chandler. They urgently seek his help in tracking down the pair. Mark Russell's primary instinct is to eliminate the threats; however, Serizawa advocates for a more nuanced approach, believing that some Titans could be benevolent. They enlist Mark’s assistance in decoding the Orca’s frequencies to locate Emma and Madison, suspecting that Jonah is using Mothra as a smokescreen to draw out all 17 tracked monsters.
The Monarch team sets out for Antarctica where Godzilla, having stirred from his slumber in the ocean depths, follows Jonah’s signals towards a three-headed Titan known as "Monster Zero." Emma ends up awakening this fearsome creature, manipulating its alpha frequency through the Orca, leading to a fierce confrontation where Monster Zero decimates several Monarch operatives, including Dr. Graham, and swiftly overpowers Godzilla.
The plot thickens as it becomes apparent that Emma was complicit with the terrorists all along, arguing that awakening the Titans is essential for Earth’s healing from human-induced damage. She insists that the battles of Titans foster new life through their radiation. In Mexico, Jonah and Emma unleash Rodan, the Fire Demon, to fight against Monster Zero, who decisively defeats Rodan before clashing again with Godzilla. During this epic showdown, the Navy employs an experimental missile called the "Oxygen Destroyer," which seemingly kills Godzilla. However, Monster Zero not only survives but also rejuvenates itself and calls forth other dormant Titans globally.
As Emma’s actions lead to her daughter's disillusionment with her, Dr. Ilene Chen (Ziyi Zhang) uncovers that Monster Zero is, in fact, Ghidorah, an ancient alien entity bent on reshaping Earth. Meanwhile, Mothra emerges from her cocoon, traveling to communicate with the recovering Godzilla in an underwater city. The team, realizing the urgency, chooses to detonate a nuclear warhead to revitalize Godzilla. In a heroic sacrifice, Serizawa detonates the warhead manually, successfully reinvigorating the legendary creature.
Later, while hiding in one of Monarch's shelters in Boston, Emma recognizes the catastrophic implications of Ghidorah and the Titans, far surpassing human destruction—yet Jonah dismisses her concern. Madison overhears their conversation and impulsively seizes the Orca device, broadcasting a calming frequency at Fenway Park that inadvertently lures the Titans towards her. Ghidorah soon descends upon Boston to destroy the Orca, yet Godzilla, supported by Monarch, engages in the battle.
As conflict ensues, Mark leads a team to rescue Madison, keenly aware that Godzilla’s rising radiation levels threaten a thermal nuclear explosion. Mothra intervenes but is challenged by Rodan, whom she ultimately defeats. Ghidorah, seemingly unbeatable, is ready to end Godzilla until Mothra sacrifices herself to empower him, abruptly revitalizing the formidable creature. Reuniting as a family, Emma, Mark, and Madison re-engage the Orca to divert Ghidorah away from Godzilla. In another act of sacrifice, Emma buys time for her family to escape, leading to Godzilla absorbing immense power, radiating a fierce red aura. With newfound strength, he vanquishes Ghidorah, disintegrating its last head, while Rodan and other Titans submit to Godzilla’s reign.
In the aftermath, news clippings and Monarch reports reveal the Titans contributing to the Earth's recovery, hinting at a possible second Mothra egg discovery, and chronicling the Titan convergence on Skull Island, along with ancient depictions of Godzilla’s clashes with Kong. In a post-credits scene, Jonah and his associates procure the severed head of Ghidorah in Mexico, suggesting that the conflict is far from over.
