Elisa Esposito, abandoned as an infant with scars on her neck, is mute and communicates through sign language. In 1962, amidst the Cold War, she works as a custodian at a secretive government lab in Baltimore, Maryland, living a routine life above a movie theater. Her closest friends are her neighbor Giles, a closeted gay struggling illustrator, and her coworker Zelda Fuller. Colonel Richard Strickland captures a mysterious amphibious creature from a South American river and brings it to the lab. Curious, Elisa discovers the humanoid creature and begins a secret bond with it. General Frank Hoyt seeks to exploit the Amphibian Man for U.S. advantage in the Space Race, despite protests from scientist Dr. Robert Hoffstetler, secretly a Russian spy named Dimitri Mosenkov, who is ordered to ensure the creature’s demise. Upon learning of the plans to dissect the Amphibian Man, Elisa tries to enlist Giles’ help to free him.

Initially reluctant, Giles changes his mind after personal setbacks and joins Elisa’s mission. Zelda, initially hesitant, also joins in to aid their escape plan. Elisa plans to release the Amphibian Man into a nearby canal during heavy rain, temporarily keeping him in her bathtub. Strickland interrogates Elisa and Zelda without success. During their escape attempt, the creature inadvertently harms Giles, but miraculously heals him, sparking Giles’ support for their cause. Elisa and the Amphibian Man develop a romantic relationship, culminating in intimacy. General Hoyt pressures Strickland to recover the creature within 36 hours or face dire consequences. Meanwhile, Hoffstetler is instructed to return to Russia soon. As the release day nears, the Amphibian Man’s health deteriorates. Hoffstetler meets his handlers, but Strickland, discovering Hoffstetler’s identity, intervenes violently. Strickland learns of Elisa and Zelda’s involvement, threatening Zelda until her husband reveals Elisa’s plan. At the canal, Strickland confronts Elisa, Giles, and the Amphibian Man, resulting in a deadly confrontation where the creature ultimately saves Elisa’s life. In a poignant conclusion, as police arrive, the Amphibian Man uses his healing abilities on Elisa, revealing they share a similar aquatic nature. They embrace, and Giles narrates that Elisa and the Amphibian Man found happiness together.