The film opens with an American military pathologist commanding a reluctant Korean assistant to violate protocol by dumping over 200 bottles of formaldehyde down the drain, which leads to the Han River. A few years later, two men are standing and fishing in Han River when one discovers a mutant amphibian (which is never shown). He releases the palm-sized creature when it bites him. Four more years later, a man commits suicide by jumping off a bridge into Han River, but not before noticing that there's "something dark, underwater."
In the present day, Park Gang-du (Song Kang-ho) is a seemingly slow-witted man who runs a snack-bar with his father, Hee-bong (Byeon Hee-bong). Hyun-seo (Ko Ah-seong) is a schoolgirl and Gang-du's daughter. Gang-du's sister, Nam-joo (Bae Doona), is a national medalist archer who has an unfortunate tendency to hesitate, and his brother Nam-il (Park Hae-il) is an alcoholic former activist who has not done much since graduating from university.
Gang-du is delivering a meal to some patrons, and sees a crowd gathering along Han River. He joins them as they stand near the side of the river and point at something under the Wonhyo Bridge. It is the creature, now grown. It drops into the water, and moves towards shore. Gang-du throws a can of beer into the water near it, and the creature grabs for the can. The other people nearby then begin to playfully toss other pieces of food to it, but the creature disappears from view. A few moments later, the creature appears on shore behind them, and begins to attack and devour people. Gang-du and an American man named Donald try to fight the creature, and successfully hit it with a street sign, Donald however, loses his arm to the creature afterwards. As Gang-du runs away, he sees Hyun-seo emerge from the snack bar and grabs her hand without stopping. He then stumbles and unwittingly grabs a different girl. A short distance away, he looks back and sees the creature pull Hyun-seo into the river. Gang-du then sees the monster dragging her on the opposite bank before disappearing into the water.
As the family mourns the young girl in a shelter set up for victims of the attack, government representatives in yellow bio-hazard suits arrive and demand to know who has had direct contact with the creature. Gang-du admits that he has, and the family is forced to the hospital, where Gang-du is quarantined. The Korean government announces that the creature is not only a direct danger, but also the host of a deadly, unknown virus that they claim infected the American whose arm had been bitten off. Gang-du receives a phone call from Hyun-seo, who is not dead, but trapped in a sewer. She is cut off as her cellphone battery runs out. Gang-du tries to explain to others, but his explanation sounds more insane than sane to the people at the hospital. Hee-bong believes his son, and uses up his life savings so that they can escape from the hospital and rescue Hyun-seo. They are then able to obtain a truck, two non-yellow hazmat suits, weapons, and a map of the sewer system around the Han River.
The family search the sewers to no avail. They return to their snack stand at the banks of the Han river to rest for the night. Hee-bong admonishes his younger son and daughter for lambasting Gang-du, admitting that his son's slow-wit was caused by him because over the years he wasn't able to provide sufficient care for his older son as he did with them. They wake to find the creature watching them. Hee-bong fires on the creature, causing it to attack them and overturn the snack stand. As the creature tries to get at them inside, Hee-bong fires a shot that causes the creature to flee. Hee-bong, Gang-du & Nam-il give chase, firing wildly. Hee-bong is eventually killed by the creature, and Gang-du is captured by soldiers; Nam-il and Nam-joo escape but are separated.
In the hospital, Gang-du overhears that there is no virus: the government is merely perpetuating a charade to save face. The American scientist who lets out the secret claims that Gang-du is infected in the brain. A team of doctors perform a frontal lobotomy on Gang-du. Afterwards, a nurse mocks the seemingly brain-damaged and unresponsive Gang-du. He suddenly takes her hostage with a syringe full of his "infected" blood, his "slow-wittedness" apparently cured by the lobotomy, and escapes to find that he is not in a hospital, but the back of a military truck on the Han River shores. He drives to Wonhyo Bridge in an ambulance.
Hyun-seo has been trapped in a deep sewer pit since she was spit out by the creature. The creature periodically drops off victims into the pit, to store for later. Hyun-seo finds all the others dead or dying except for a young street urchin named Se-ju. Nam-il goes to a college friend for help, and traces Hyun-seo's phone call. He is betrayed for reward money, but cleverly escapes. Before losing consciousness under a bridge, he sends a text message with Hyun-seo's location to Nam-joo. Nam-Joo goes to the bridge, but comes across the creature. She is near enough that she has a shot, but just as she has the creature in her sights, she hesitates. The creature runs past her and she is knocked unconscious. Hyun-seo tries to climb out of the sewer by a rope fashioned from her and other victims' clothes, but the creature snatches her and places her back on her feet. The camera cuts to black as the creature pounces on her and Se-ju.
Gang-du discovers the feeding pit only in time to see the creature dashing away with a child's arm dangling from its mouth. He chases it on land as it dives into the river. Nam-il wakes to see a homeless man who has been tending to him, and with the man's help and liquor, he makes several Molotov cocktails and together they take a taxi to the Wonhyo Bridge. Nam-joo also awakes. She sees the creature and Gang-du run past her and follows them. The three siblings are led to the riverbank, where the creature attacks demonstrators protesting the government's use of Agent Yellow - a chemical weapon highly harmful to humans - against the creature (and non-existent virus). Police press back the demonstrators, trying to hold them back. The crowd finally disperses as the creature comes near to the shoreline. All three siblings meet up briefly on top of the bridge, but Gang-Du leaps from the bridge to chase the creature.
Agent Yellow is released and incapacitates the creature temporarily. Pushing through the poisonous fumes, Gang-du pulls out the two seemingly lifeless children from the creature's mouth. Hyun-Seo had grabbed the other child and had avoided being fully swallowed by grabbing onto a large tooth but the three siblings discover she has suffocated. The creature revives and tries to return to the river. Enraged, Gang-du grabs a street sign and begins to battle the creature. Nam-il also begins to throw his Molotov cocktails at it. The creature, apparently terrified of fire, continues to flee. The homeless man whom Nam-il met appears and douses the creature with gasoline, but Nam-il accidentally drops his last bottle as he attempts to throw it. Nam-joo picks up one of the lit fragments with her arrow and shoots it into the creature's eye, causing it to burst into flames, screaming in agony. The creature makes a last attempt to flee towards the protection of the river, but Gang-du finally kills it by shoving the street sign through its mouth, piercing its brain.
As Nam-joo and Nam-il mourn over their dead niece, Gang-du manages to revive Se-ju. In the epilogue, we see Gang-du and Se-ju living as a family in the rebuilt and cozy-looking snack bar, sometime in the winter. One night Gang-du believed he saw something move outside. He gets his rifle but then sets it down, believing it was his imagination. A televised US Senate press release - claiming that the Korean "disease crisis" was caused by "misinformation" - is drowned out by their conversation. The child asks him to turn it off, as he finds it boring, and they eat dinner.
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