After their victory over the Incas, the Spanish conquerors advanced around the middle of the 16th century into the northwest of present-day Argentina, which had belonged to the Inca Empire for about 50 years. The native population groups continued to resist the Spaniards for a long time, for example in the Guerras Calchaquíes between 1560 and 1667.

On 16 April 1582, Hernando de Lerma founded San Felipe de Lerma en el Valle de Salta on behalf of the Spanish Crown. It was one of several new settlements in a region that had strategic importance for the Spanish because of the transportation routes and communications between Peru, the rich Potosí (now Bolivia) and the Río de la Plata. After Hernando de Lerma fell into disgrace, his name was erased from that of the city, which was then called only San Felipe el Real or Ciudad de Salta. The word Salta comes from the indigenous people, which means that it existed before.

Salta initially belonged to the Viceroyalty of Peru and from 1776 to the newly established Viceroyalty of Río de la Plata. When the Spanish crown created the province of Salta del Tucumán in 1783, Salta became its capital.

The May Revolution of 1810 in Buenos Aires began the years-long struggle for independence from Spain. The Salta City Council soon joined Argentina's first independent government (Primera Junta de Gobierno). After the defeat of the patriots in the Battle of Sipe Sipe in 1811, the city and its surroundings became a center of defensive warfare against the royalists advancing from Peru. Legendary are the guerrilla battles of the gauchos led by their general Martín Miguel de Güemes from Salta. In 1813, the Ejército del Norte under the command of General Manuel Belgrano defeated the royalist army in Salta.

After the Argentine War of Independence, the city was economically ruined. It was not until the end of the 19th century that the economy began to take off with the settlement of numerous Spanish, German, Italian, Lebanese and Syrian immigrants and the construction of a railroad line.