The defeat of Lempira's revolt, the establishment of the bishopric (first at Trujillo, then at Comayagua after Pedraza's death), and the decline in fighting among rival Spanish factions all contributed to expanded settlement and increased economic activity in the 1540s. A variety of agricultural activities was developed, including cattle ranching and, for a time, the harvesting of large quantities of sasparilla root. But the key economic activity of sixteenth-century Honduras was mining gold and silver.

The initial mining centers were located near the Guatemalan border, around Gracias. In 1538 these mines produced significant quantities of gold. In the early 1540s, the center for mining shifted eastward to the Río Guayape Valley, and silver joined gold as a major product. This change contributed to the rapid decline of Gracias and the rise of Comayagua as the center of colonial Honduras. The demand for labor also led to further revolts and accelerated the decimation of the native population. As a result, African slavery was introduced into Honduras, and by 1545 the province may have had as many as 2,000 slaves. Other gold deposits were found near San Pedro Sula and the port of Trujillo.

By the late 1540s, Honduras seemed headed for relative prosperity and influence, a development marked by the establishment in 1544 of the regional audiencia (see Glossary) of Guatemala with its capital at Gracias, Honduras. The audiencia was a Spanish governmental unit encompassing both judicial and legislative functions whose president held the additional titles of governor and captain general (hence the alternative name of Captaincy General of Guatemala). The location of the capital was bitterly resented by the more populous centers in Guatemala and El Salvador, and in 1549 the capital of the audiencia was moved to Antigua, Guatemala.

Mining production began to decline in the 1560s, and Honduras rapidly declined in importance. The subordination of Honduras to the Captaincy General of Guatemala had been reaffirmed with the move of the capital to Antigua, and the status of Honduras as a province within the Captaincy General of Guatemala would be maintained until independence. Beginning in 1569, new silver strikes in the interior briefly revived the economy and led to the founding of the town of Tegucigalpa, which soon began to rival Comayagua as the most important town in the province. But the silver boom peaked in 1584, and economic depression returned shortly thereafter. Mining efforts in Honduras were hampered by a lack of capital and labor, difficult terrain, the limited size of many gold and silver deposits, and bureaucratic regulations and incompetence. Mercury, vital to the production of silver, was constantly in short supply; once an entire year's supply was lost through the negligence of officials. By the seventeenth century, Honduras had become a poor and neglected backwater of the Spanish colonial empire, having a scattered population of mestizos, native people, blacks, and a handful of Spanish rulers and landowners.

Data as of December 1993