For his feats in the conquest of Mexico the Spanish Crown granted Francisco García Holguín land in the northeastern part of the island from the Jigüe to the Marañon Rivers in 1545, prompting García Holguín, his wife Isabel Fernández de Sandoval, and some followers, to found the first village in the area.

Historians say that García Holguín returned to Mexico where he had large extensions of land and died there. Throughout time the village was then surrounded by several other areas called Managuaco, Los Guazumas (Guasimas), Las Cuevas, Cayo Llano and others, and on April 3rd, 1720, on the eve of Saint Isidoro, a church was inaugurated in the urban area, dedicated to Our Lady of the Rosary. In 1752 other churches were added:  San Idelfonso and San Miguel which gave names to other streets (today known as Aricochea and Luz Caballero).

Spanish King, Ferdinand VI, granted the Title of City to Holguin back on January 18th, 1752. This action resulted in the recognition of the social and commercial growth of the village set up in 1545 by Captain Garcia Holguin when he was granted the land and built the first houses.  In 1752, according to historians, the city had a population of 1291 whites and 135 slaves, 211 rustic houses and one public school.  

The northern part of Holguín between Auras and Gibara was also attacked by the English Navy in the mid-18th century, but Holguineros defended it fiercely, causing more than 70 casualties among the English troops, resulting in the English Navy pullout.

In 1863 there were already 76 sugar mills in the area, 753 tobacco plantations and hundreds of farms worked by slaves, evidence of the area’s economic and social growth.