In 1556, a determined Don Aguirre (Édgar Ramírez) commands a group of Spanish conquistadors in their perilous journey to South America, driven by the hope of discovering the Lágrimas De Cristal Tree. This mythical tree is said to possess flowers that can cure diseases, heal wounds, and lift curses — a chance to save his ailing daughter. As many conquistadors fall victim to their quest, the resilient Puka Michuna tribe steps in to heal the surviving soldiers using the tree's miraculous blooms. However, when the tribe's chief refuses to disclose the tree's location to Aguirre, who believes that possessing a sacred Arrowhead will lead him to it, Aguirre responds with violence, brutally killing the chief and setting the village ablaze. In a final act of vengeance, the dying chief curses the conquistadors, condemning them to an immortal existence, unable to stray far from the Amazon River without being pulled back by the jungle.
Fast forward to 1916 London, where Dr. Lily Houghton (Emily Blunt) presents her groundbreaking research on Tears of the Moon to the Royal Society, with her brother MacGregor (Jack Whitehall) by her side. Desperate to revolutionize medicine and assist in the British War Effort, the Houghtons seek permission to study an artifact — an arrowhead linked to the legendary tree. Their request is denied, as the tree is dismissed as a mere myth and female scientists are typically overlooked. Undeterred and believing the arrowhead and her ancient Amazon map hold the secrets to finding the tree, Lily undertakes a daring theft. She narrowly escapes the clutches of Prince Joachim (Jesse Plemons), an ambitious German royal who has financed a military expedition with mercenaries to seize the tree for Germany’s war aims and pursue immortality.
Upon arriving in the First Brazilian Republic, Lily and MacGregor set out to find a capable guide to traverse the perilous waters of the Amazon. Their search leads them to Nilo (Paul Giamatti), the harbormaster, but they find themselves colliding with Frank Wolff (Dwayne Johnson), a cynical yet ultimately noble steamboat captain. Frank is notorious for offering jungle cruises filled with exaggerated dangers and cheesy jokes but currently faces trouble as his engine is repossessed by Nilo over unpaid debts. In a twist of fate, Lily walks in on Frank attempting to reclaim his engine while misunderstanding him for Nilo. During lunch, she strikes a deal for 20,000 reais, while MacGregor scrambles to negotiate a higher price of 50,000 reais for the expedition.
Initially hesitant to embark on such a perilous journey, Frank's interest piques upon seeing the arrowhead around Lily's neck — a relic he knows all too well. After he drops his price to 10,000 reais and unexpectedly rescues MacGregor from a leopard attack—who turns out to be his pet—the trio prepares to set off. However, their adventure takes a chaotic turn as they escape an impending threat from Joachim's submarine, who is determined to reclaim the Arrowhead.
As the journey unfolds, Lily discovers a trove of Frank's sketches and inventions linked to her research. A growing distrust blooms between them when she realizes Frank had manipulated her fears for his gain. They soon find themselves in the clutches of the Puka Michuna tribe, led by Trader Sam (Veronica Falcón), who reveals the arrowhead’s secrets, including the tree's blooming cycle — triggered only by a blood moon.
Meanwhile, Joachim, persistent in his pursuit, seeks out the long-lost conquistadors, petrified yet alive beneath the earth. He manages to negotiate their release from their stone prisons, with promises of flowers. The resurrected conquistadors set out to capture Lily, but their own curse restricts them to the river’s edge. In a complex twist of fate, Frank, it is revealed, is among the cursed, having turned against Aguirre to defend the tribe against his tyranny.
As events spiral, all parties converge at the La Luna Rota Waterfall, where the tree is finally located. A climactic struggle ensues, with Frank and Lily racing against time to save each other and thwart Joachim's ambitions. During the chaos, Lily learns about her true feelings for Frank and ultimately gives up the magical flower to free him from his curse. As dawn breaks, they emerge victorious, with Frank deciding to leave his old life behind and join Lily.
With their return to Britain, Lily ascends to the status of a full professor at the University of Cambridge. The siblings share a bond even stronger than before, while Frank embraces a new chapter filled with love and adventure alongside Lily as they explore the wonders of London together.
