In the years since Godzilla's emergence resulting in the destruction of San Francisco, humanity finds itself at odds with what to do as more super species of creatures, dubbed Titans, are discovered.
Dr. Emma Russell (Vera Farmiga), a paleobiologist working for the crypto-zoological agency Monarch, believes humans and these Titans can co-exist peacefully. To do so she has developed a device called the Orca that can communicate with them; however, in the process of testing the device on a newly born Titan, she and her 14-year-old daughter Madison (Millie Bobbie Brown) are kidnapped by an eco-terrorist organization bent on using her technology to locate and traffic Titan DNA.
With the Orca now in the wrong hands, Moncarch directors Dr. Ishiro Serizawa (Ken Watanabe) and Dr. Vivienne Graham (Sally Hawkins) seek out Mark Russell (Kyle Chandler), Emma's estranged husband and Madison's father, who left the organization following their son's death in the San Francisco attack. Having co-developed the Orca, he is best suited to tracking down the device and his family.