The remnants of a Taíno settlement in the region, Los Buchillones, constitute the most complete pre-Columbian remains in the Greater Antilles, but Ciego de Ávila only really wrote itself into the history books in the early 1500s. The province got its present name from merchant Jacomé de Ávila, who was granted an encomienda (indigenous workforce) in San Antonio de la Palma in 1538. A small ciego (clearing) on Ávila's estate was put aside as a resting place for tired travelers, and it quickly became a burgeoning settlement.

Throughout the 16th and 17th centuries the northern keys provided a refuge for pirates fresh from lucrative raids on cities such as Havana. During the 19th century, the area was infamous for its 68km-long Morón–Júcaro defensive wall: constructed to prevent marauding Mambís (19th-century rebels) from forging a passage west. Come the 1930s, Señor Hemingway became the region's most celebrated holiday-maker: Papa (Ernesto) fished and even tracked German submarines in the waters off Cayo Guillermo. Thousands more foreign visitors followed, particularly after the mega-hotel construction on the cayos which began in the early 1990s.