The film opens at an unspecified date in the early 21st century. During construction on the London Underground, workers penetrate a cave. A huge dragon emerges from hibernation, incinerating the workers with its breath. The only survivor is a boy, Quinn Abercromby (Ben Thornton), whose mother, Karen (Alice Krige)—the construction crew chief—is crushed to death protecting him. The dragon flies out of the Underground, and soon more dragons appear. It is revealed through newspaper clippings and the narration that dragons are the species responsible for the extinction of the dinosaurs. They are speculated to hibernate after destroying most living creatures until the planet repopulates. Mankind's militaristic resistance, including nuclear weapons in 2010, only hastens the destruction, and by 2020, humans are nearly extinct.
Quinn (Christian Bale) leads a community of survivors at Bamburgh Castle, Northumberland. They are starving while awaiting harvest. Although most trust Quinn, some are restless and defiant. Eddie (David Kennedy) and his group steal a truck to pick tomatoes, though it is too soon for harvest. They are attacked by a dragon. One man is killed and the rest are surrounded by fire. Quinn, Creedy (Gerard Butler), and Jared (Scott Moutter) rescue them with old fire engines, but the dragon kills Eddie's son before escaping.
The Kentucky Irregulars, a group of Americans led by Denton Van Zan (Matthew McConaughey), arrive in a armored convoy with a Chieftain tank and a AgustaWestland AW109 utility helicopter, the latter of which is piloted by Alex Jensen (Izabella Scorupco). Van Zan has a system for hunting dragons and knows their weakness: poor vision during twilight. With Quinn's help, Van Zan, Alex, and their team hunt and slay the dragon who destroyed the crops.
The survivors enjoy a celebration at the castle that night but Van Zan is embittered by the loss of three of his men. Van Zan and Alex tell Quinn that all the dragons they have found have been female. The Americans believe there is only one male—if they kill it, the dragons can no longer reproduce. Although Quinn knows about the male dragon, which killed his mother, he refuses to help.
In open defiance, Van Zan orders his soldiers to enlist the castle's best men despite Quinn's argument that if they find the male it will kill them and find the castle, the men remain hesitant at Van Zan's request. Quinn attacks Van Zan in front of the castle's inhabitants and a fight to the death ensues, Van Zan gives Quinn a terrible beating and it's left for the watching crowd to pull Van Zan off before Quinn is beaten to death, Van Zan giving Quinn the beating has an impact on the castle's inhabitants, Van Zan and indeed some of the castle's men then depart with Quinn bloodied and helpless to stop them, but true to Quinn's warnings Van Zan's caravan is attacked by the dragon in the ruins of a town 66 miles (106 km) from London. The dragon then finds the castle and kills most of the inhabitants. Quinn gets the survivors to a bunker, but they are trapped when the dragon returns; during its final attack, Creedy is killed.