- Based on Disneyland's theme park ride where a small riverboat takes a group of travelers through a jungle filled with dangerous animals and reptiles but with a supernatural element.
- 1916. Dreaming about saving countless lives and having another adventure, the feisty English feminist and doctor of botany, Dr Lily Houghton, embarks on a peril-laden mission to change the world. Along with her fashionable brother, MacGregor, Dr Houghton enlists the help of the arrogant, wisecracking riverboat skipper, Captain Frank Wolff, to guide them through the serpentine Amazon River in La Quila, his swift wooden boat. Now, as the intrepid trio ventures deeper and deeper into the heart of an impenetrable green maze, searching for something that cannot be found, a centuries-old curse and the ruthless aristocrat, Prince Joachim, threaten to put an end to their ambitious plans. And, sooner or later, the jungle always wins. Is it true that the Spanish conquistador, Don Aguirre, was lost in the same God-forsaken part of the world?—Nick Riganas
- In 1556, Don Aguirre (Édgar Ramírez) leads Spanish conquistadors to South America to search for the Lágrimas De Cristal Tree, whose flowers cure illness, heal injuries, and lift curses. He wants a cure for his dying daughter. After many conquistadors die, the Puka Michuna tribe heals the sickened survivors with the Tree's flowers. When the tribal chief refuses to reveal the Tree's location (by giving Aguirre the sacred Arrowhead which is the key to finding the location of the magical Tree), Aguirre stabs him and burns the village. The dying chief curses the conquistadors, making them immortal and unable to leave sight of the Amazon River without being dragged back by the jungle itself.
In 1916 London, Dr. Lily Houghton's (Emily Blunt) Tears of the Moon research is presented by her brother MacGregor (Jack Whitehall) to the Royal Society. The Houghtons, hoping to revolutionize both medicine and the British War Effort, request access to a recently acquired arrowhead artifact, but the request is denied as the Tree is considered myth and female scientists are disfavored. However, believing the arrowhead and her old Amazon map are the key to finding the Tree, Lily steals it, narrowly evading Prince Joachim (Jesse Plemons) (A deranged and ambitious German royal who finances and leads a military expedition with mercenaries to claim the Tree of Life, both to aid Germany's war effort and achieve immortality), who is equally intent on finding the Tree for Germany. Joachim had paid the Royal Society in solid gold bars to acquire the Arrowhead.
Arriving in the First Brazilian Republic, Lily and MacGregor search for a guide to navigate the Amazon River. They were scheduled to meet the harbormaster Nilo. Frank Wolff (Dwayne Johnson) (A shrewd and cynical but ultimately noble steamboat skipper who reluctantly agrees to guide two explorers on their quest for the mythical Tree) who offers jungle cruises embellished with faked theatrical dangers and corny puns to tourists. Frank returns to port and has his engine repossessed by Nilo due to failure to pay off the loan on time. Frank steals back his repossessed boat engine from the harbormaster Nilo (Paul Giamatti).. Lily reaches Nilo's office, while Frank was in it stealing his engine back. She assumes Frank to be Nilo. They sit down for lunch and Lily negotiates a price of 20K real. Meanwhile MacGregor finds the real Nilo and negotiates a price of 50K reals. Frank initially declines, citing the dangers of the river and jungle. Frank reconsiders upon seeing the arrowhead hung on a thread around Lily's neck. Lily knows that Frank lied to her, but she agreed to go with him when he drops his price down to 10K reals and then saves Macgregor from a leopard who attacked them inside the restaurant. After the attack, Frank increases his price to 15K reals. Turns out the leopard was Frank's pet. The trio departs after escaping from Joachim's U-boat, which was hiding in the river. Joachim's goons try to abduct Lily, but she escapes, and Joachim was determined not to let the Arrowhead leave the harbor.
In Frank's cabin, Lily finds photos and sketches of modern inventions as well as research on the Tears of the Moon. She accuses him of seeking the Tree, but he insists he gave up long ago. They are captured by the Puka Michuna tribe, disguised as cannibals, but quickly release them as they were hired by Frank. Angered, Lily begins to doubt Frank (as Frank used the terror of Puka Michuna to extract the Arrowhead out of Lily). The tribal chief Trader Sam (Veronica Falcón) (the female chief of the Puka Michuna tribe, who is a longtime friend of Frank's and knows about the curse) translates the symbols on the arrowhead, revealing the Tree's location and that it only blooms under a blood moon.
Meanwhile, Joachim decides to ask the only other people who have come close to this quest. He has located the conquistadors, petrified inside a cave. He makes them agree to find the arrowhead for him in exchange for flowers. He diverts the river to free them and they are reanimated while fused with rain-forest elements. The conquistadors track down and attack the tribe where Frank is stabbed through the heart. Lily flees with the artifact, but vines pull the Spaniards away when they unknowingly lose sight of the river while pursuing her. Since the conquistadors cannot pursue Lily and Frank, they send a message to Joachim about their location.
To the Houghtons' amazement, Frank reappears alive. He reveals he is one of the cursed conquistadors, who once wanted to help find the Tears to save Aguierre's paralyzed daughter. However, he sided with the tribe against Aguirre's rampage. Aguirre hated Frank for his betrayal and hunted him again and again. After years of fighting, Frank trapped his vengeful comrades away from the river's view, petrifying them. Failing to find the Tree, Frank became a tour guide.
Lily and Frank continue to La Luna Rota Waterfall and uncover a submerged temple. Meanwhile, Joachim has captured MacGregor and forces him to reveal Lily's location. Frank, the Houghtons, the Germans, and the conquistadors all converge at the Tree when La Luna Rota's water is partially drained. Frank agrees to help Joachim to bloom the tree, if he allows him one petal to break his curse. Lily also wants one petal to help Joachim, and he agrees.
Discovering the arrowhead is a locket with a red gem inside, Lily places the two pieces into carvings in the bark and the Tree briefly blooms under the blood moon. As a fight ensues, Lily recovers one flower. The German soldiers drown, Joachim is crushed by falling rock, and Frank crashes his boat to block the river, petrifying himself and the rest of the conquistadors to save Lily. Realizing her true feelings for Frank, Lily sacrifices the flower to lift Frank's curse and restore his mortality, and he decides to leave the Amazon to be with her. The moon's last beam blooms a single flower, which Lily takes for research. Returning to port, Frank sells his business to Nilo.
Upon their successful return to Britain, Lily becomes a full professor at the University of Cambridge. MacGregor rejects an invitation of membership from the Royal Society. Lily and Frank then explore London together.
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