The Valle de Sula is one of the longest-inhabited regions of Honduras. A village site excavated in the early 1990s along the Río Ulúa was dated to 1100–900 B.C. Little is known about the site’s builders, other than they had some apparent contact with the Olmecs of central Mexico, suggesting a fairly high degree of development.

The Maya are believed to have maintained settlements along the Valle de Sula, but their presence in what is modern-day Honduras was mainly limited to the region farther west and south, near the present Guatemalan border. The largest Indian settlement in the region, which the Spanish saw when they first penetrated the interior of Honduras, was at Naco, in a small valley on the south side of the Sierra Merendón from San Pedro.

La Villa de San Pedro was founded on June 27, 1536, by Pedro de Alvarado, conqueror of Guatemala, on the flat area of the Valle de Sula, far enough from the edges of the Ríos Chamelecón and Ulúa to protect the settlement from flooding. An early base of operations for the Spanish in their conquest of Honduras, San Pedro quickly faded in importance during the middle and late colonial period. After 1600, San Pedro was virtually abandoned, in part because of pirate and Indian attacks and also because colonists had moved on in the Spaniards’ search for gold and silver in the highlands.

During the later part of the colonial era, San Pedro was a base for local cattle-ranchers and a collection center for sarsaparilla, a root that grew wild in the region and at the time was considered a miracle drug by Europeans, who believed it cured venereal diseases.

In the mid-19th century, San Pedro’s fortunes took a turn for the better when commerce picked up at the port of Omoa, and San Pedro became a frequent stop-off point for goods on their way in or out of the country. But it was the growth of the banana industry and the reopening of Puerto Cortés in the late 19th century that jump-started San Pedro’s economy, and it has continued growing steadily.