The island of Key Largo is one of the largest of the Florida Keys islands. Though originally inhabited by native tribes, Key Largo and the other islands were eventually overrun by Europeans. Though it is not known when Europeans first landed on any of the islands, explorer, Ponce de Leon made note of them in his logs. The name "keys" is believed to have originated from the Spanish word , cayo, meaning "small islands."

Until 1763, Florida was under Spanish rule, but was traded with Britain for Havana. Though jurisdiction over the key islands was at first uncertain, Britain essentially claimed them as part of Florida, and this was never contested. The islands were returned to Spain in 1783, but in 1821, both mainland Florida and the islands became U.S. territories. For almost 100 years, inhabitation of Key Largo and its sister islands was rare and sporadic.

As early as 1826, there was a "lightship" stationed at the northern end of Key Largo for the purpose of warning ships of the dangerous coral reefs nearby (a lighthouse was constructed on the island in 1852). 

Access to the islands was limited to boat travel until the early 1900s, when tycoon, Henry Morrison Flagler instituted the Florida East Coast Railway, completed in 1912. In 1935, this network was destroyed by a hurricane and was replaced and modernized in 1938 by the Overseas Highway, with numerous bridges that connect the islands.