A documentary film crew headed by anthropologist Steve Cale (Eric Stoltz) and director Terri Flores (J. Lo) travel down the Amazon River in search of a mysterious Indian tribe. On their journey they save a man, Paul Sarone (Jon Voight), from a sinking boat. He offers to help in their search for the tribe, but he is actually a snake-hunter looking for the legendary Anaconda snake. When an accident leaves Cale unconscious, Sarone takes charge of the boat, leaving the rest of the crew in grave danger.