In 1899, a terrorist group led by the Fantom cause international tension, breaking into the Bank of England to steal Leonardo da Vinci’s blueprints of Venice’s foundations, and then kidnap German scientists. The British Empire sends Sanderson Reed to Kenya to recruit adventurer and hunter Allan Quartermain. Quartermain, retired following the death of his son, at first refuses until a group of assassins are sent to kill him. In London, Quartermain meets “M”, who is forming the latest generation of the League of Extraordinary Gentlemen. He reveals the Fantom plans to start a world war by bombing a secret meeting of world leaders in Venice. The new League consists of Quartermain, Captain Nemo, vampiric chemist Mina Harker, and invisible thief Rodney Skinner.
The League travel to the London docks to recruit Dorian Gray, Mina’s former lover who is kept immortal thanks to a missing portrait. The Fantom’s assassins attack, but the League fend them off, aided by U.S. Secret Service Agent Tom Sawyer. Dorian and Sawyer join the League. They then capture Edward Hyde in Paris and he joins the League after being offered amnesty, transforming back into his alter ego Dr. Jekyll. The League travel for Venice in Nemo’s submarine, the Nautilus, but it soon becomes clear there may be a mole on board, a camera’s flash powder being found in the wheelhouse, and one of Jekyll’s transformation formulas disappears. Suspicion falls on the missing Skinner.
The Nautilus arrives in Venice just as the bombs go off, causing the city to start collapsing in a domino effect. Sawyer uses Nemo’s automobile to stop the destruction, while Quartermain confronts the Fantom, who is unmasked as M. Dorian is also revealed to be the traitor, murdering Nemo’s first mate Ishmael, and steals the Nautilus’ exploration pod. M and Dorian leave a phonograph recording for the League, revealing their true goal is to ignite the world war and Dorian has been collecting physical elements of the League to create superhuman formulas and sell them off to the highest bidder. The Nautilus is damaged by bombs hidden on board, but Hyde saves it by draining the flooded engine rooms. Skinner sends a message to the League, revealing he has snuck aboard the exploration pod and to follow his heading.
The League reach northern Mongolia, reuniting with Skinner, where they plot to destroy M’s factory with explosives. Nemo and Hyde rescue the scientists, Skinner sets the explosive charges, while Mina battles Dorian, killing him by exposing him to his portrait. Quartermain and Sawyer confront M, identifying him as Professor James Moriarty, taking on a new alias after his alleged death at Reichenbach Falls. Sawyer is taken hostage by an invisible Reed, Quartermain shooting the latter, only for Moriarty to fatally stab him. Moriarty flees outside but Sawyer successfully shoots him, the formulas sinking into the icy water.
Quartermain is buried beside his son in Kenya. The surviving League members recall how a witch doctor had blessed Quartermain for saving his village, promising that Africa would never let him die. The remaining League members depart, and said witch doctor arrives, performing a ritual that summons an unnatural storm, with a bolt of lightning ambiguously striking Quartermain’s grave.