Ridley Scott, director of Alien, has teleported from the land of stomach-exploding aliens to that of the New World. 1492: Conquest of Paradise telescopes Christopher Columbus's (Gerard Depardieu) four journeys to the New World into two. After seven long years of looking for people to fund his expedition, Columbus persuades Queen Isabel (Sigourney Weaver) to grant him the necessary money and privileges to embark on his journey. Led by conflicting passions of "god, gold, and glory" to explore a new route to China, Columbus stumbles upon some islands off the coast of North America. He imagines the new land around him as an earthly paradise that Spain can colonize and call her own. But there is a slight problem: Native Americans already occupy the lands. Much of the first voyage and landing concerns Columbus trying to gain the natives' trust and his establishing a fort in a town he names La Navidad (The Nativity). Before departing, Columbus lets the natives know that he will return again with thousands of Spaniards. The natives are not amused and explain to Columbus that they realize his primary interest is in their gold.

Upon returning to the New World for his second voyage, Columbus finds his paradise turned into an earthly hell: the entire village of Navidad has been killed. Soon afterwards, the natives are enslaved to greater degrees to hunt for gold; one of Columbus's men, Moxica (Michael Wincott), leads a rebellion; a hurricane, an unknown phenomenon to Spaniards, destroys his colony; the natives begin fighting their oppressors. Columbus's dream evaporates under the pressure of the Conquest's desire for blood and gold. Columbus is removed from his post and returned to Spain in chains. Although he is granted permission by Queen Isabel for a third voyage, Columbus never gains Spain's recognition for his discovery of the New World.