Known on many early Spanish charts as Cayo de Dose Leguas - SP. "Key of Twelve Leagues", or more simply as Cayo Largo. Caio des 12 Leguas on the Vingloons map of Cuba. (1639) A Dutch chart drawn by Johannis Van Kevlen in 1712 shows Cayo de Doze Leguas. Cayo Largo on Juan Elixio de la Puente's 1765 chart. DeBrahm map (1771) shows Peninsula Larga. William Roberts, in his "First Discovery and Natural History of Florida" (1763) uses Cayo Largo 0 Doce Leguas.

Visited by Bernard Romans in 1774. According to J.W. Norie, in his "Piloting Directions for the Gulf of Florida, the Bahama Banks & Islands" (1828) Key Largo was uninhabited at that time: "Cayo Largo affords no living creature, except racoons and insects, especially those troublesome ones, mosquitos and scorpions." The first modern settlements were in the Tavernier area, around the time of the Civil War. The settlement area was first known as Lowesport, after the Lowe family, and later was called Planter. The main community on Key Largo was called Rock Harbor, as was the Post Office. The post office name was changed to Key Largo in 1952, after the motion picture starring Humphrey Bogart became a hit.