Anaconda begins by introducing us to a film crew. They are on the verge of meeting and filming a once thought lost tribe of people located on the edge of the Amazon river. The film crew slowly but surely makes their way deeper and deeper into the rain forest when they chance upon a lone man on a wrecked boat. Under the hope that the stranger knows about the native tribe's location, they take him upon their ship.
Shortly after the rescue, the film crew's captain suffers a debilitating wasp sting to his throat while underwater attempting to free the ship from a mass of vines, knotting up the boat's propeller. Once the captain is out of commission, the rescued stranger starts acting exactly like that, strange.
Unbeknownst to the film crew, the stranger is a snake hunter obsessed with finding and killing a large anaconda snake in the area. He begins to start leading the crew towards where he believes the snake to be instead of where the native tribe is supposed to be located.
As they get deeper into the amazon, the elusive anaconda starts to pick off the crew one by one. The snake hunter then uses this to gain one ally from the film crew, who helps the snake hunter keep the remainder of the crew under control, including the new ally's girlfriend.
The partnership is short lived as the anaconda makes a snack of the traitorous crew member. This allows the rest of the crew to physically overpower the snake hunter and to tie him up. The snake hunter then goads the girlfriend of the most recent victim into getting near him to kill him. He manages to choke her into unconsciousness before stealthily dumping her body overboard, where she drowns.
The anaconda at this point returns and throws the crew into disarray. It kills one more member of the original film crew before being shot and killed. With one enemy down, the film crew also dispatches of the snake hunter and they attempt to continue on.
The snake hunter however was not killed. He catches up to the last two film crew members and captures them and uses them as bait for an even larger, second anaconda. The snake takes the bait and the snake hunter springs his trap. The rope trap is no match for the snake who breaks free with relative ease. In the meantime, the film crew members are escaping from their bonds. The snake kills the snake hunter and is dramatically burned to death by the last two survivors.
The survivors continue as best as possible on their path and do find the native tribe they had been originally looking for.