Gyo opens with a crew of fishermen aboard a trawler dragging up a number of strange-looking fish in the boat’s net. Upon trying to inspect the unusual creatures, they discover that the strange fish seem to have legs. The fish then suddenly scuttle away, diving back into the ocean.
Meanwhile, in Okinawa, Tadashi, a young man, and his girlfriend Kaori arrive on the island to enjoy a scuba-diving vacation. Encountering a fish with legs, Kaori, who has a hyper-sensitive sense of smell, becomes irritated by its smell and begs Tadashi to get rid of it. He seals it in a bag, but it manages to escape. The next day, large amounts of marine life with legs invade Okinawa, including a legged great white shark which menaces the protagonists. Tadashi and Kaori manage to return to Tokyo, although Kaori becomes irritated and paranoid, claiming to smell the fish. They both encounter the bagged fish they originally encased and present it to his uncle, Doctor Koyanagi.
A short while later, Tadashi returns to find Koyanagi missing an arm. As he was examining the machine in detail, it used a series of spikes and tubes to latch on to his arm, forcing him to amputate it. The walking machine scuttles into the room, now carrying Koyanagi’s arm instead of the fish. Koyanagi is fascinated by this discovery, and then reveals that the fish was the result of the Japanese Army’s World War II research into a virus that causes its host to produce a deadly and repulsive stench in a desperate effort to turn the tide of the war. His father developed a “walking machine”, which pumps the virus into a host and causes the host to release the gas which powers the machine’s movement; walking machines were built to carry the hosts further, allowing them to reach and sicken enemy troops.
However, enemy aircraft sank the ship carrying the prototypes for the walking machines. Soon, Kaori and Tadashi discover that hordes of marine life with legs are invading Tōkyō, having gradually invaded the Kantō region. Infected by the gas, Kaori becomes depressed by her stench, and attempts to commit suicide. Tadashi takes her to Koyanagi in an effort to save her but plunges into a canal where he passes out after being injured by thousands of small walking fish. Awakening one month later, he discovers that Koyanagi has placed her into a custom-built walking machine. Upon switching the machine on, Koyanagi is mortally wounded by Kaori, who quickly escapes.
Searching for her, Tadashi notices that most of the walking fish have decayed, and that the walking machines are now carrying infected citizens instead. Journeying through Tōkyō, he encounters a circus, where he learns from the ringmaster that the gas appears to be alive, taking on a soul-like appearance when ignited. Tadashi encounters Kaori and rescues her from one of the acts at the circus and takes her to Koyanagi’s Lab. There Koyanagi’s assistant, Ms. Yoshiyama, reveals that Koyanagi has died from his wounds. When she attempts to remove the walking machine from Kaori, Koyanagi appears, now mutated by the infection and attached to a modified walking machine with an airship that allows him to fly. Kaori notices Tadashi and Ms. Yoshiyama together and attempts to attack her. During the uproar, Koyanagi manages to capture Ms. Yoshiyama and fly away.
Large groups of walking machines attack Kaori, and Tadashi becomes lost in his attempt to save her. He continues to search for her, when he notices the circus troupe attack Koyanagi’s airship, which springs out wings and escapes. Tadashi encounters a group of students from Kyōto University, who explain that they are immune, and that the virus created the walking machines after synthesizing them from shipwrecks. He joins the students in their research to defeat the virus and save humanity. As they walk together, he encounters Kaori’s burnt remains and remarks that she is free from the smell.
The series tells the story of the citizens of Kurouzu-cho, a fictional city which is plagued by a supernatural curse involving spirals. The story for Uzumaki originated when Ito attempted to write a story about people living in a very long terraced house, and he was inspired to use a spiral shape to achieve the desired length. Ito believes the horror of Uzumaki is effective due to its subversion of symbols which are positively portrayed in Japanese media, and its theme of protagonists struggling against a mysterious force stronger than themselves.