When a documentary crew traveling through the Amazon jungle, picks up a stranded man, they are unaware of the trouble that will occur. This stranger's hobby is to capture the giant Anaconda snake, and plans to continue targeting it on their boat, by any means necessary.

In New York, the ambitious Dr. Jack Byron and his associate Gordon Mitchell present the research of his assistant Sam Rogers to the CEO and board of directors of a corporation to sponsor a scientific expedition to Borneo. The objective is to find a flower, Blood Orchid, that flourishes for a couple of weeks every seven years and could be a fountain of youth, prolonging the expectation of life of human beings. They are succeeded and once in Borneo, they realize that it is the raining season and there is no boat available to navigate on the river. They pay US$ 50,000.00 to convince Captain Bill Johnson and his partner Tran to sail to the location. After an accident in a waterfall, the survivors realize that a pack of anacondas have gathered for mating and their nest is nearby the plantation of Blood Orchid, which made them bigger and bigger.

Picking up immediately where Anaconda 3 left off, herpetologist Amanda Hayes finally learns her employer Murdoch's true colors when he hires a doctor to harvest a fresh supply of blood orchids to experiment with the regenerative nectar on a baby snake in order to seek treatment for his own terminal illness. Amanda is forced to secretly bring together another team of scientists whom face off against a heavily armed squad of Murdoch's men to steal the coveted orchids before the killer Anaconda hunts both parties down.