Precolonial and colonial times

At various times before the 19th century, people who were related or subject to the Calusa and the Tequesta inhabited Key West. The last Native American residents of Key West were Calusa refugees who were taken to Cuba when Florida was transferred from Spain to Great Britain in 1763.

Cayo Hueso is the original Spanish name for the island of Key West. Spanish-speaking people today also use the term when referring to Key West. It literally means 'bone cay', cay referring to a low island or reef. It is said that the island was littered with the remains (bones) of prior native inhabitants, who used the isle as a communal graveyard. This island was the westernmost Key with a reliable supply of water.

Between 1763, when Great Britain took control of Florida from Spain, and 1821, when the United States took possession of Florida from Spain, there were few or no permanent inhabitants anywhere in the Florida Keys. Cubans and Bahamians regularly visited the Keys, the Cubans primarily to fish, while the Bahamians fished, caught turtles, cut hardwood timber, and salvaged wrecks. Smugglers and privateers also used the Keys for concealment. In 1766 the British governor of East Florida recommended that a post be set up on Key West to improve control of the area, but nothing came of it. During both the British and Spanish periods no nation exercised de facto control. The Bahamians apparently set up camps in the Keys that were occupied for months at a time, and there were rumors of permanent settlements in the Keys by 1806 or 1807, but the locations are not known. Fishermen from New England started visiting the Keys after the end of the War of 1812, and may have briefly settled on Key Vaca in 1818.