Cancer-terminal tycoon Peter Murdoch's secret Wexel Hall Pharmaceuticals lab has developed a blood orchid extract cure. To examine why it works optimally in snakes, they also bread a super-anaconda strain. But the original pair escapes, leaving a bloody trail of corpses. Murdoch runs, instructing his staff to clean up. They keep failing and being eaten like unsuspecting locals, some alive, even after enlisting ruthless big game hunter Hammett. The fast-growing pregnant monster sheds its skin, thus disabling the only tracking device.

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.