The original name given the Florida Keys was Los Martires or "the martyrs," since they appeared as men who were suffering. No one knows exactly when the first European set foot on one of the Keys, but the islands soon became prominent on nautical maps. The nearby treacherous coral reefs claimed many actual seafaring "martyrs" from the time of early recorded history. Many Spanish ships sailing from Central and South America ended up broken on the reefs along the islands.

Many of the first settlers to the Florida Keys were attracted by the chance to salvage cargo from the many ships lost here, and were known as "Wreckers." Some of the less scrupulous of these wreckers would help the process along by lighting fires in locations to mislead the mariners into dangerous waters, but nature needed little help to ensure frequent opportunities for salvage.

In 1763 Spain ceded Florida to the British in exchange for the Port of Havana, but the Florida Keys were not mentioned in the treaty. Spain did not choose to actively contest the British claim that the Keys were part of Florida and eventually Florida was returned to Spain following the Revolutionary war in an effort to keep it out of American hands. This effort failed 58 years later when the United States purchased Florida from the Spanish.

Shortly after the United States purchased the Florida territory in 1821, the U.S. Navy established the first base in Key West to combat piracy in the Florida Straights and the Gulf of Mexico. At the same time, farmers from the Bahamas settled on Key West, former British Loyalists who had left after the Revolutionary war. Fishermen from Connecticut and more settlers from the Bahamas settled on Marathon shortly afterwards. Because of its strategic placement, Key west was the largest city in Florida by the 1880's, although most of the rest of the Florida Keys were mostly empty, with only one or two families on any of the other islands.

The Florida Keys were inaccessible except by boat until Henry Flagler's Florida East Coast Railway was extended from Homestead, Florida to Key West, completed in 1912. An estimated 50 million passengers travelled from the extension before it was destroyed in 1935 by a hurricane that brought devestation to much of the central Keys and killed over 500 people with its 200 mph winds and 17 foot storm surge. The surviving portions of the railroad formed much of the foundation for the Florida Overseas Highway, which was completed in 1938.