Elisa Esposito, who was found abandoned by the side of a river as an infant with scars on her neck, is mute and communicates through sign language. In 1962, during the Cold War, Elisa works as a custodian at a secret government laboratory in Baltimore, Maryland, and lives a very routine life in an apartment above a movie theater. Her only friends are her closeted gay next-door neighbor Giles, a struggling middle-aged advertising illustrator, and her co-worker Zelda Fuller.
Colonel Richard Strickland has just captured a mysterious creature from a South American river and has taken it to the Baltimore facility for further study. Curious, Elisa discovers it is a humanoid amphibian. She begins visiting him in secret, and they form a close bond.
Seeking to exploit the Amphibian Man for a US advantage in the Space Race, General Frank Hoyt is eventually persuaded by Strickland to vivisect it. Dr. Robert Hoffstetler, a scientist who is secretly a Russian spy named Dimitri Mosenkov, pleads unsuccessfully to Strickland to keep him alive for further study, while simultaneously ordered by his Soviet handlers to kill the creature.
When Elisa overhears the Americans’ plans for the Amphibian Man, she attempts to persuade Giles to help her liberate him. He refuses at first, scared of the consequences and ethics. After failing to get his job back, Giles is rejected by a pie restaurant worker, who he discovers is a racist and homophobe. Subsequently, he has a change of heart.
Hoffstetler stumbles upon Elisa’s plot in progress and chooses to assist her. Though initially reluctant, Zelda also becomes involved in making the escape successful. Elisa plans to release the Amphibian Man into a nearby canal when heavy rain will allow access to the ocean. In the meantime, she keeps him in her bathtub. Strickland interrogates Elisa and Zelda, among others, but he learns nothing.
The Amphibian Man encounters one of Giles’s cats, who reacts expectedly. Giles discovers the Amphibian Man devouring the cat. When he tries to stop him, he gets startled, slashes Giles’s arm and rushes out of the apartment. He gets as far as the cinema downstairs before Elisa finds him and returns him to her apartment.
The creature touches Giles on his balding head and wounded arm. The next morning, Giles discovers hair has begun growing back on his previously bald head, while the wounds on his arm have healed. Elisa continues to develop her romantic relationship with the Amphibian Man, culminating in sexual intercourse.
General Hoyt unexpectedly arrives and tells Strickland he has 36 hours to recover the Amphibian Man, or his career and life will be over. Meanwhile, Hoffstetler is told by his handlers that he will be extracted from the US in two days. Although the planned release date approaches, the Amphibian Man’s health begins to deteriorate.
Hoffstetler goes to meet his handlers, and Strickland follows him. At the rendezvous, Hoffstetler is shot by one of them and Strickland intervenes, shooting both handlers. Realizing that Hoffstetler is a spy, Strickland tortures the dying man into revealing the Amphibian Man’s whereabouts. He is surprised to learn that Elisa and Zelda are involved.
Strickland threatens Zelda in her home unsuccessfully, until her husband Brewster reveals that Elisa has the Amphibian Man. She immediately telephones her, warning her to release the creature. An enraged Strickland ransacks Elisa’s empty apartment until he finds evidence in the bathtub and a calendar note revealing where she plans to release the Amphibian Man.
At the canal, Elisa and Giles are bidding farewell to the creature when Strickland arrives, knocks Giles down, and shoots both the Amphibian Man and Elisa. The Amphibian Man heals himself, and kills Strickland by slashing his throat. As the police arrive on the scene with Zelda, the Amphibian Man takes Elisa and jumps into the canal, swimming around her lifeless body. He applies his healing powers/ability to the scars on Elisa’s neck, which open to reveal gills like his.
Elisa jolts back to life and they embrace and kiss. In a closing voice-over narration, Giles conveys his belief that Elisa lived happily ever after and remained in love with the Amphibian Man.
