Tegucigalpa became a site of major interest for the Spanish in the late 16th century due to its location and mineral wealth, particularly silver. In 1578, Spanish explorers and settlers officially claimed the area, integrating it into the Spanish colonial empire in Central America. The claim was part of a wider strategic initiative to assert control over regions rich in resources that could sustain the Spanish economy and empire. Spanish explorer Alonso de Cáceres played a pivotal role during this period, leading expeditions that sought to explore and secure resource-rich territories. His activities were backed by the Spanish Crown, which was eager to expand its dominion and profit from new territories. As Tegucigalpa transitioned into a colonial city, numerous indigenous communities faced upheaval, experiencing significant cultural and social transformations as a result of Spanish settlement policies and resource extraction practices.

The establishment of Spanish authority led to the beginning of extensive mining operations, predominantly focused on silver extraction, which would have long-lasting economic implications for the region. Tegucigalpa's strategic position in the mountainous region allowed for effective transport and communication routes, further cementing its role as a centralized area for Spanish administrative efforts in Honduras. Over time, Tegucigalpa would emerge as a vital urban center within colonial Honduras, shaping the sociopolitical landscape for centuries to come and paving the way for its future role as the national capital.