Following the events in Rio de Janeiro where Monarch failed to prevent a large-scale Titan tragedy, the organization has been placed under direct government control. As the world recovers, Godzilla and Kong are called to face a new threat of cosmic proportions that risks triggering a second massive awakening of Titans across the globe and destroying the entire planet. The central antagonist is SpaceGodzilla, a mutated clone of Godzilla from outer space making its debut in the MonsterVerse.

The story begins with Monarch now operating under governmental oversight after its previous failures. Dan Stevens returns as Trapper Beasley, the Titan veterinarian from the previous film. The human cast includes Kaitlyn Dever, Jack O'Connell, Delroy Lindo, Matthew Modine, Alycia Debnam-Carey, and Sam Neill, with several actors portraying new characters navigating the escalating crisis. The teaser campaign, set in a call center in Sedona, Arizona, references the location where the spider-like Titan Scylla previously reawakened.

Filming took place across multiple international locations including Queensland and Gold Coast in Australia, Moab Utah standing in for Sedona Arizona, Mexico City featuring locations such as Paseo de la Reforma and the Palacio de Bellas Artes, central London, and Mumbai. The production aims to address previous criticisms regarding human characters while maintaining the focus on the iconic Titans as they unite against a world-ending extraterrestrial menace.