Tegucigalpa was founded by Spanish settlers as Real Villa de San Miguel de Heredia de Tegucigalpa on September 29, 1578 on the site of an existing native settlement. Before and after independence, the city was a mining center for silver and gold. The capital of the independent Republic of Honduras switched back and forth between Tegucigalpa and Comayagua until it was permanently settled in Tegucigalpa in 1880.

A popular myth claims that the society of Comayagua, the long-time colonial capital of Honduras, publicly disliked the wife of President Marco Aurelio Soto, who took revenge by moving the capital to Tegucigalpa. A more likely theory is that the change took place because President Soto was an important partner of the Rosario Mining Company, an American silver mining company, whose operations were based in San Juancito, close to Tegucigalpa, and he needed to be close to his personal interests.

Tegucigalpa remained relatively small and provincial until the 1970s, when immigration from the rural areas began in earnest. During the 1980s, several avenues, traffic overpasses, and large buildings were erected, a relative novelty to a city characterized until then by two-story buildings. Tegucigalpa continues to sprawl far beyond its former colonial core, towards the east, south and west, creating a large but disorganized metropolis.

The city's main buildings include the former Presidential Palace, which is now a national museum, a 20th-century Legislative Palace, the headquarters of the Central American Bank for Economic Integration, the campus of the National University of Honduras founded in 1847, an 18th-century cathedral, and the Basilica of the Virgin of Suyapa.

Industrial production, small and mostly for local consumption, has increased since the 1970s with improved roadways. Products include textiles, clothing, sugar, cigarettes, lumber, plywood, paper, ceramics, cement, glass, metalwork, plastics, chemicals, tires, electrical appliances, and farm machinery. Some maquiladora duty-free assembly plants have been established since the 1990s in an industrial park in the Amarateca valley, on the northern highway. Silver, lead and zinc are still mined in the outskirts of the city.