John Whitney, an anthropologist for the Field Museum of Natural History in Chicago, travels to a distant South American tribe to study their ways and samples a soup the tribesmen offer him. Afterward, he confronts a ship’s captain, urging him to remove a cargo bound for Chicago. The captain refuses, unwilling to delay the voyage, so Whitney quietly slips aboard. When he cannot locate the intended cargo, he raises the alarm, leaving the ship to soundly depart into the sea.
Six weeks pass, and the vessel finally reaches Lake Michigan with its crew unaccounted for. Chicago PD lieutenant Vincent D'Agosta and his partner, Sergeant Hollingsworth, begin to piece together a grim mystery as they uncover dozens of corpses stacked in the ship’s bilge.
Seven days later, Margo Green, an evolutionary biologist, arrives at the museum to find competition for a research grant already heating up with her colleague Greg Lee. After the ship’s crates are brought to the museum, Margo and her mentor, Albert Frock, inspect them and discover they are mostly empty aside from a bed of leaves and a stone statue of the legendary forest creature, the "Kothoga." A peculiar fungus on the leaves draws their attention, and the leaves themselves are incinerated. That night, a security guard named Frederick Ford is killed in a manner mirroring the ship’s demise, signaling to D'Agosta that a link exists. Believing the killer remains inside the museum, he orders it sealed to allow investigators to work, even as the museum’s director, Ann Cuthbert, pushes back for the sake of a high-profile upcoming exhibition.
Margo deduces that the fungus contains concentrated hormones found in several animal species. In the container of leaves, she uncovers a mutated beetle carrying a mix of insect and reptilian DNA, which had slipped into the shipment earlier. When she crushes the mutant with a heavy book, the connection sharpens. Ford’s autopsy reveals a disturbing detail: his hypothalamus was removed, just like the ship’s bodies, strengthening the theory of a single, horrifying killer on the loose. In the museum’s basement, the police confront a disturbing scene as they confront a mentally ill, homeless ex-convict; they shoot him dead and discover Ford’s wallet and a crew ID tag on him, leading them to believe the killer perished. Despite this, D'Agosta remains skeptical, but pressure from Mayor Robert Owen and museum security chief Tom Parkinson forces him to proceed with the exhibition.
On opening night, D'Agosta orders a lockdown of the museum’s areas except for the main exhibition hall. Frock and Margo, trapped in the laboratory wing, continue their work and determine that Ford’s killer is pursuing the leaves’ hormonal content. D'Agosta and a handful of officers search the basement tunnels once more, but are attacked by the creature, losing K-9 Officer Bradley and the police dog. With chaos erupting, D'Agosta instructs Hollingsworth to evacuate the guests, yet the panic worsens as the headless body of a murdered officer drops into the crowd. The alarms trip, causing the security system to misbehave and strand a small group inside. Two security guards who attempt to restore power are killed by the unseen intruder.
D'Agosta reunites with Margo and Frock in the lab as the monstrous Kothoga, a fearsome chimera, breaks through the ceiling and attacks them. They seal a steel door to block its path. Margo hypothesizes that the fungus mutated a smaller creature, while Frock contends that in the absence of the leaves the Kothoga would instinctively hunt for human hypothalami until it has exhausted its prey. He further speculates that the tribe knew about the fungus and may have used it to control a threat before lying in wait, only to fall silent as the danger disappeared. The Kothoga dies of “starvation” when it can no longer find sustenance. D'Agosta discovers a radio and instructs Hollingsworth to guide the museum’s guests through an old coal tunnel. Tom Parkinson, Greg, and benefactors Mr. and Mrs. Blaisedale refuse to retreat, with CPD officer McNally choosing to stay behind to guard them; the Kothoga returns to the main hall and murders them along with SWAT team members who enter through the skylights.
Margo proposes using liquid nitrogen to kill the Kothoga, given its partial reptilian traits and cold-blooded tendencies. While gathering the remaining leaves in the lab, they discover Frock has been killed. In the sewer tunnels, D'Agosta uses the leaves to lure the Kothoga away from the coal tunnel, enabling the guests to escape, though Officer Bailey and a guest are killed in the exchange. Yet liquid nitrogen proves ineffective against the creature. Margo and D'Agosta flee, racing toward safety.
In the lab, Margo’s computer finishes analyzing the Kothoga’s human DNA, revealing a startling truth: John Whitney is the Kothoga, transformed after drinking the tribesmen’s soup.
The Kothoga bursts into the lab through the ceiling, with D'Agosta barred outside. It pursues Margo, who faces it alone, and then halts as if recognizing her. In a desperate move, Margo starts a fierce fire, incinerating the creature, which survives only by concealing itself inside a maceration tank. As dawn arrives, a team of police break into the lab and rescue Margo from the tank, finding only the charred remains of the Kothoga.
