The Gulf of Guacanayabo (Spanish: Golfo de Guacanayabo) is a bay along the southern coast of Cuba, bordered by Granma and Las Tunas provinces. It is located at .
The largest port on the bay is Manzanillo, ad to the north-west, the gulf is bordered by the Jardines de la Reina archipellago. Cuba's longest river, the Cauto River empties in the Gulf of Guacanayabo.
It is also where, in 2005, Hurricane Dennis had its peak effect.