In the year 1899, a shadowy band of men, disguised as German soldiers, executes a bold heist at the prestigious Bank of England, stealing precious layouts of Leonardo Da Vinci's vision for Venice's foundations. Following this audacious act, they are led by their enigmatic leader known only as the "Fantom". Stepping up the tension between nations, these impostors masquerade as British officers to kidnap German scientists and demolish a factory, bringing the United Kingdom and Germany dangerously close to war. The scene is set with cutting-edge weaponry (for the era), including tanks and rapid-firing machine guns.
Against this backdrop, Sanderson Reed of the British Empire journeys to Kenya with a pressing mission. He seeks out the world-famous hunter and adventurer, Allan Quatermain, played by Sean Connery, who has retreated into a life of solitude, deeply mourning the tragic loss of his son from a past expedition. Initially, Quatermain has no intention of aiding the British Empire again, but fate intervenes when armed assailants attempt to assassinate him, coercing him to reluctantly join forces with Reed.
Upon arriving in London, Quatermain encounters "M", Reed's superior, who lays bare the Fantom's sinister plot to obliterate Venice, thereby thwarting a pivotal summit of world leaders. M outlines the scheme: to ignite a global conflict and an arms race from which the Fantom stands to gain enormous profits. To counter the Fantom’s threat, a formidable coalition known as the League of Extraordinary Gentlemen is being assembled, featuring Quatermain himself, Captain Nemo (portrayed by Naseeruddin Shah), the brilliant chemist Mina Harker (played by Peta Wilson), and the elusive invisible thief Rodney Skinner (embodied by Tony Curran).
The mission takes an unexpected turn as the League must recruit their fifth member—the everlasting Dorian Gray (played by Stuart Townsend), who boasts a unique curse where he remains eternally young while a missing portrait of him ages. Once infatuated with Mina, Dorian's initial response is one of refusal to participate. However, when the Fantom and his henchmen stage an ambush, the unexpected intervention of U.S. Secret Service Agent Tom Sawyer turns the tide, allowing them to vanquish the attackers, albeit with the Fantom slipping away.
As the plot thickens, it is revealed that Mina is not merely a chemist but a powerful vampire, a transformation born from her haunting history with Count Dracula. Eventually, both Dorian and Sawyer opt to join the League, embarking on a journey aboard Captain Nemo's formidable submarine, the Nautilus, to locate their last member, Mr. Hyde (played by Jason Flymeng).
Upon reaching Paris, the League captures Hyde, making a deal that grants him amnesty for his sordid crimes in exchange for his allegiance. Hyde complies and reverts to his more benign persona, Dr. Jekyll. However, suspicion looms within the team as signs of treachery begin to surface, including the discovery of flash powder from a camera in the ship's control room and the disappearance of one of Jekyll's transformative formulas. With Skinner falling under suspicion of being the saboteur, he mysteriously vanishes.
When they finally reach Venice, it becomes evident that the city's very foundations are crumbling, setting off a deadly cascade of destruction due to bombs secretly planted beneath its surface. Recognizing that immediate action is vital, Nemo formulates a risky plan to avert disaster by targeting one of the buildings out of order with the Nautilus's formidable missiles. Quatermain, along with Sawyer, Mina, and Dorian, rushes to outpace the impending chaos, while Dorian and Mina courageously leap from Nemo's vehicle to engage the Fantom's forces in a fierce battle. A confrontation with the Fantom unveils his true identity as M, leading to a deadly missile launch that ultimately saves the remnants of Venice.
However, tragedy strikes when Dorian returns to the Nautilus only to murder Nemo's faithful first mate, Ishmael, revealing his hand as a traitor. The League discovers M's treachery; M had intended to exploit the unique abilities of the team to forge superhuman formulas to sell to the highest bidder, using their capabilities for his dark ambitions while only requiring Quatermain to capture Hyde.
The explosive finale unfolds with a dramatic confrontation where M is revealed to be the infamous Professor James Moriarty. Amidst chaos, Mina bravely confronts Dorian and slays him by exposing his hidden portrait, which allows him to age and perish. Meanwhile, Nemo and Hyde come face-to-face with Moriarty’s goons, leading to a fierce skirmish. Quatermain finds himself battling Moriarty, who reminds him of Sawyer's invisibility due to Reed's machinations.
As Quatermain is mortally wounded in a fierce struggle, Sawyer employs the teachings of Quatermain to execute a precise shot, bringing down Moriarty as the stolen formulas are forever lost beneath icy waters. Quatermain's life comes to a poignant close, imparting his wisdom to Sawyer about the passage of time and legacy in a world on the brink of a new era.
In the end, Allan Quatermain is laid to rest in Kenya, next to his son. While the remaining League members share tales of their fallen comrade, a witch doctor—a figure from Quatermain’s past, who owes him a debt for saving his village—performs an enigmatic ritual at his grave. A dramatic bolt of lightning strikes Quatermain's resting place, leaving his fate shrouded in mystery and sparking hope that his spirit endures as long as the heart of Africa beats.