The earliest settlement in the current area of Cayo Hueso dates back to the second half of the 16th century, following the burning of Havana by French pirate Jacques de Sores.

[5] Modern sights include the art deco Edificio Solimar, built in 1944; the Casa Marina, a former brothel; and the Fragua Martiana Museum, dedicated to the "father" of the Cuban nation, José Martí.

In 1984, the Cuban government began allowing rent money to count towards the purchase of properties, which led to generalized improvements to many buildings in Cayo Hueso.

[10] Cayo Hueso is home to various cultural sites such as the Callejón de Hamel, an alleyway decorated since 1990 by Salvador Gonzáles Escalona, in which events such as workshops and rumba performances take place regularly.

[14] Among the musicians born in Cayo Hueso are trumpeters Félix Chappottín and Mario Bauzá, singers Omara Portuondo and Sara González Gómez, and percussionist Pedrito Martínez.