Following the events of the previous film, a baby anaconda is captured and used by Peter "J.D." Murdoch to craft a serum for cell regeneration by blending the blood orchids from Borneo. The test initially seems to work, allowing the baby Dracanaconda to regenerate, but Murdoch burns the creature in a blaze of science and ambition. When he disappears, the enormous anaconda escapes its enclosure and leaves a trail of danger, eventually killing Peter in a mine thick with blood orchids.
[Peter "J.D." Murdoch], a billionaire battling bone cancer, responds by unleashing his ruthless arsenal: his assassin Eugene and a squad of mercenaries to locate Peter and the serum he created, hoping it will cure him. Alongside them, the lone survivor of the prior snake attack, Dr. Amanda Hayes, and two officers set out with a shared goal: destroy the serum and kill the snake. Their path leads them to the rugged Romanian Carpathians, where they encounter Alex, a trekker pursuing a paleopathology project among the ruins and mines.
In the mine, the crew discovers the blood orchids and Amanda wastes no time wiring the area with explosives to destroy the orchids’ habitat. The ancient predator seems to outmaneuver them, attacking the group and leaving two officers seemingly dead. Amanda, ever the quick thinker, tricks the snake into triggering a cave-in that appears to kill it, but the victory is short-lived: she is knocked unconscious and Alex escapes to summon help.
Meanwhile, a separate group of explorers—Jackson, his girlfriend Heather, Heather’s best friend Wendy, and the brothers Patrick and Scott—are drawn into the chase. The serum’s power has made the anaconda effectively immortal, regenerating even after devastating damage, so their hopes for a quick end are dashed as the beast regrows from the cave-in.
Heather falls ill after a spider bite, and the very next day the mercenaries Marauding Murdoch hired clash with the expedition, with the snake preying on the group and killing one of them. Amanda and Alex regroup after she saves him, and the duo eventually reunites with the explorers, witnessing the snake rip away Patrick’s arm in a brutal display of its relentless resilience.
The pursuit intensifies as Eugene and his henchmen close in on Hayes and Jackson’s party. When Amanda resists sharing information about the serum, Eugene shoots and kills Patrick. In the chaos, Wendy tries to escape but is shot dead by Eugene, a blow that ignites Jackson’s fury.
With time running out, Amanda and Scott press on to find the serum, aided by two henchmen who accompany them to locate the original supply. They reach Peter’s house and uncover the serum, though they keep much of it hidden for the moment. The anaconda storms the house, devouring one gunman, while the other fights for his life. Amanda and Scott slip away and discover more serum stored in a shed.
Back at the base, Murdoch returns to claim the serum. He confronts Vasile, a stubborn officer who survived the earlier encounter and turns out to be Murdoch’s rival for the research. Murdoch orders Eugene to kill him, but Eugene refuses, revealing that Vasile had offered him more money to switch sides. When Vasile orders Eugene to kill Murdoch, Jackson seizes the opportunity to stab Eugene; the gun goes off, killing Vasile in the ensuing chaos. The last mercenary, Armon, is knocked aside by Jackson, and the confrontation leaves Jackson wounded as Armon is about to strike. Amanda shoots Armon dead, ending that threat.
Murdoch presses for the serum, and Amanda finally gives it to him. He injects himself, and the serum appears to work, but the moment the other party breathes a sigh of relief, the snake arrives and rips Murdoch’s head from his shoulders. Amanda destroys the remaining orchids in a decisive blast, and the survivors attempt to escape by jeep as the snake gives chase.
Eugene, who somehow clung to the back of the vehicle, assaults them during the ride. Jackson fights him in the rear, allowing Amanda to kick Eugene out of the car with two grenades in hand. The grenades detonate as the snake closes in and annihilate both Eugene and the monster in a vicious explosion. In a final, unsettling twist, the anaconda seems to regenerate even from ash and slips back into the woods, leaving the fate of the monstrous creature uncertain and the survivors to press on in a world where some fears never truly die.
