Somewhere in the Brazilian rain forest, Anthropologist John Whitney (Lewis Van Bergen) witnesses an Aboriginal tribal ritual, performed by dancing men in a state of trance. He drinks a kind of potion, concocted by the tribe's witch (Montrose Hughes) using leaves with a kind of red fungal growth on them. After drinking it, he becomes hysterical at the sight of a native, dressed in a costume and wearing face-paint. Whitney says to himself: "Oh my God! It's Kathoga!"
Later, Whitney shows up at a commercial dock, where a cargo ship named the Santos Morales, is ready to depart. Locating the ship's captain (Santos Morales), Whitney pleads with him to unload his crates, destined for the Chicago Natural History Museum. Refusing to help, the captain boards the ship. Stowing away on board, Whitney locates the ship cargo hold and pries open one of the wooden crates. Finding only rugs inside, he breaks down and screams in despair. As the ship sails away, several more crates sit on the dock, labeled: "John Whitney - Chicago Natural History Museum".
A title card reads: "Six Weeks Later", as the same cargo ship arrives in Chicago. The dock is cordoned off by police and we meet Lt. Vincent D'Agosta (Tom Sizemore) as he boards the ship with Detective Hollingsworth (Clayton Rohner). There are bloodstains everywhere, and the crew appear to be all gone. Searching the cargo hold, D'Agosta finds several of the crew in the bilge - their heads severed from their bodies. D'Agosta is very superstitious and carries a "lucky bullet" for protection.
Meanwhile, the Museum of Natural History in Chicago is busy preparing for the grand opening of a new exhibit which explores the origins of superstition. As Dr. Margo Green (Penelope Ann Miller), an evolutionary biologist, arrives at work, the museum curator, Dr. Ann Cuthbert (Linda Hunt) tells Margo she is in competition for a grant, which she needs to continue her research at the museum. To her chagrin, Margo's colleague, Greg Lee (Chi Muoi Lo), has applied for the same grant. The grant is provided by wealthy Museum benefactors, the Blaisedales (Constance Towers & Francis X. McCarthy), who will attend the upcoming gala to open the new exhibit.
Stopping by the office of Dr Albert Frock (James Whitmore), a colleague of John Whitney, Margo is intrigued by the contents of several crates, recently sent by airfreight from Brazil (the crates left behind by the ship). The remnants of a stone artifact are wrapped in the green leaves used in the potion. Margo takes some of the leaves to analyze them, while the remainder are incinerated in the basement of the museum.
As a school group on an excursion enters the museum, two boys, skipping school for the day, sneak into the museum unnoticed, and hide. Alone in the museum after closing, they notice a bad smell in a basement stairwell, and discover the body of a Security Guard (Jophery C. Brown), which alerts the authorities to a killer on the loose. The guard has been beheaded and his brain removed by the killer.
While an investigation gets underway, led by Lt. Vincent D'Agosta, the stone artifact found inside the crates is gradually restored by a technician (Lynn A. Henderson), for the new "Superstition" exhibit. It is revealed later to be a depiction of the mythical "Kathoga". As Albert Frock explains, Kathoga was a Chimera - a mythical creature that combined various animals into one.
The coroner Dr. Zwiezic (Audra Lindley) examines the beheaded corpse of the Security Guard, with D'Agosta present, and discovers the victim's brain weighs less than it should. It appears to be missing the hypothalamus and pituitary glands. D'Agosta later finds out the beheaded victims on board the cargo ship were also missing the same parts of their brains.
As police continue to search the museum for the killer, a homeless man, living in the cavernous basement, is shot and killed by accident. When he turns out to be a convicted rapist and felon, the museum's head of security is satisfied. But D'Agosta isn't convinced. There is still no explanation for the missing hypothalamuses, or, the deaths aboard the cargo ship. But with the Mayor of Chicago (Robert Lesser) and his wife (Diane Robin) due to attend the opening night gala as guests of honor, D'Agosta bows to pressure and lets the event go ahead, but insists on heavy police presence.
As the gala gets underway, Margo analyzes the leaves and discovers a link between the substance on them and the human hypothalamus. The red substance contains a concentrated dose of the same hormones secreted by the hypothalamus, enough to cause rapid mutation in animals or insects that feed on it. When a beetle gets inside the container where the leaves are stored, it grows to the size of a rat, overnight. Margo shows her findings to Dr Albert Frock, who assists with her analysis of the beetle's DNA. He subscribes to a theory called the "Calysto Effect" - a sudden jump in evolution which results in an aberrant species.
Meanwhile, D'Agosta orders a search of the subterranean tunnels and old sewage system under the museum, which links up with the docks. Something in the tunnel kills a search dog and his handler, so D'Agosta orders Detective Hollingsworth back to the museum to evacuate the guests. But it's too late.
As the VIPs finally enter the Superstition exhibit, the killer strikes again, setting off a panic. The security system locks down the museum, trapping almost everyone inside. While police try to break in and helicopters lower a SWAT Team onto the roof, D'Agosta orders the remaining guests into the tunnels, which lead to the outside.
The Blaisedales elect to stay behind in the museum's main exhibit hall, along with the ambitious Greg Lee and the head of security. But they soon become victims of the Kathoga, which finally reveals itself. As the SWAT Team drops into the hall, they too are killed by the beast, which climbs walls and uses giant pincers to sever their heads.
Locked in another wing of the museum, Margo and Dr Albert Frock discover the origin of the beast, which is a hybrid of insect, reptile and various other animals, including one human being - the missing John Whitney. As the Kathoga, he must consume huge quantities of the hormones found in the human hypothalamus, to survive.
Finding Margo alive and Dr Frock dead, D'Agosta asks Margo how to kill the beast. They try unsuccessfully to freeze it in the tunnel, using liquid nitrogen, then flee back to the lab. D'Agosta orders Margo to lock herself in, while he goes after the beast, but the Kathoga outwits them and drops through the roof of the lab. While D'Agosta is locked on the other side of a metal door, Margo incinerates the Kathoga when she blows up her lab, using flammable chemicals as fuel, while hiding inside a metal container filled with water.