In the year 1899, a group of men disguised as German soldiers launches a daring attack on the Bank of England, seizing precious blueprints crafted by the legendary Leonardo Da Vinci for Venice's foundations. Soon after, another group, led by the enigmatic Fantom, dons British officer uniforms to abduct German scientists and obliterate a factory, heightening tensions between the United Kingdom and Germany—an escalation that threatens the peace and risks plunging the world into war. Both attacks showcase cutting-edge weaponry of the era, including tanks and machine guns.
Meanwhile, Sanderson Reed of the British Empire makes a journey to Kenya, where he seeks out the famed hunter and adventurer Allan Quatermain (Sean Connery). Grieving for his son lost in a previous expedition, Quatermain is reluctant to return to service. However, when assassins attempt to end his life, he finds himself no choice but to cooperate with Reed.
In London, Quatermain meets M, Reed’s superior, who reveals the Fantom's nefarious plot to destroy Venice to prevent a global leaders' meeting, with the end goal of igniting a world war to profit from arms sales. To counter this threat, a coalition known as the League of Extraordinary Gentlemen is formed, comprising Quatermain, Captain Nemo (played by Naseeruddin Shah), chemist Mina Harker (Peta Wilson), and the invisible thief Rodney Skinner (Tony Curran).
M dispatches the team to enlist their fifth member, the immortal Dorian Gray (Stuart Townsend), who remains eternally young while a hidden portrait of himself ages away. Although Dorian shares a past romantic interest with Mina, he initially refuses to join their cause. However, following an onslaught from the Fantom's assassins, aided by U.S. Secret Service Agent Tom Sawyer, the group manages to fend them off, though the Fantom escapes.
Revelations arise as it comes to light that Mina has been transformed into a vampire following her past encounter with Count Dracula. Eventually, Dorian and Sawyer join the League, embarking on Captain Nemo's submarine, the Nautilus, to retrieve their final member, Mr. Hyde (Jason Flemyng). After capturing Hyde in Paris, Quatermain cleverly persuades him into the fold by promising him clemency for his previous transgressions.
As their journey progresses towards Venice, tensions mount aboard the Nautilus when strange occurrences hint at a traitor among them, particularly when a camera's flash powder is found in a precarious spot and one of Dr. Jekyll's transformation potions goes missing. Suspicion falls on Skinner, but he mysteriously vanishes.
Upon reaching Venice, the team is met with chaos as bombs detonated beneath the city kickstart a catastrophic chain reaction, jeopardizing its very foundations. Captain Nemo deduces that they can thwart this calamity by targeting a building out of sequence with one of the Nautilus' missiles. In a race against time, Quatermain, Sawyer, Mina, and Dorian take Nemo's vehicle to outpace the disaster, with Dorian and Mina leaping into the fray against the Fantom's henchmen. Quatermain confronts the Fantom, ultimately revealing him to be M, just as Sawyer manages to launch the missile, thereby saving what's left of Venice.
However, trouble brews as Dorian kills Nemo's first mate Ishmael and it becomes clear that both Dorian and M are traitors, escaping in a capsule. A recorded message from M discloses his true ambition—collecting the unique abilities of the League members to create superhuman formulas for profit. Amidst this turmoil, bombs detonated aboard the Nautilus lead to significant harm, but Hyde exhibits his supernatural abilities to save the day by draining the flooded engine rooms.
The Nautilus navigates the Amur River in northern Mongolia, where the League reconnects with Skinner. He informs the group about M's clandestine factory producing armed versions of the Nautilus and weaponized mutants. In an ambitious mission, the League splits up to take down M’s operations while liberating the kidnapped scientists and their families.
Quatermain and Sawyer track down the now-revealed Professor James Moriarty, while Mina ultimately confronts and defeats Dorian by exposing his portrait, leading to his demise. As the League battles through M's forces, they learn that Sawyer has been captured, instigating a final showdown where Quatermain is gravely injured. As he lays dying, he imparts wisdom to Sawyer, signaling the torch has now passed to the new century.
With Quatermain laid to rest in Kenya beside his fallen son, the remaining League members share tales that ensure he will never truly perish, thanks to a blessing from a witch doctor. As they depart, a powerful bolt of lightning strikes his grave, rendering his fate uncertain and leaving behind a legacy of courage and adventure.
