The region known today as Santiago del estero was inhabited by numerous tribes. Some were sedentary, resided in permanent form on the ground and others were nomadic tribes who lived off hunting, fishing and pillage. On the base of the testimony of the first chroniclers, the diaguitas occupied the region west of the county, wihch at present time belong to the Rio Hondo, Guasayán, Choya and Jiménez districts. For their customs, they resembled to the juríes, however, they were less prone to fight against their neighbors. They belonged to the Andean area and their culture was the most developed in the region. The lules, tribes from Chaco, occupied the area where of Pellegrini, Jiménez, Rio Hondo and part of Alberdi, Copo and Figueroa districts. They were nomadic people and very belligerent, they lived off the hunt, of fishing and robbery.

The sanavirones, occupied the Southwest of the county: the departments of Ojo de Agua, Quebracho, Atamisqui and part of Loreto, Mitre and Avellaneda. They limited with the domain of the comechingones, inhabitants of the mountains of Cordoba. While the indamás occupied the southeast of the province, everything or at least part of what today are the districts of Rivadavia, Mitre and Aguirre, also extending up to the frontier with the comechingones. The salavines, it is believed, a partiality of the sanavirones, and their center was probably located in the District of Salavina. The plunderings of the nomadic chaqueñas hunting tribes who populated the Chaco Santiagueño, are attested by the towns of the villages of the Matara district. In this complex group of indigenous stand out the vilelas, tufas, tonocotés, chulupíes who extended from the Salado Norte, many times surpassing the river. Also, the guaycurúes and avipones who belonged to the culture guaranítica, occupied the oriental side of the province. They invaded the present districts of Copo, Alberdi, Moreno, Matara, General Taboada, Belgrano, Aguirre, Mitre, Quebrachos and Rivadavia. Around the X century, in the region well-known as the Mesopotamia Santiagueña, some farming and pottery cultures relatively advanced were developed: Averias, Mercedes and Sunchituyoj. The aborigins inhabited towns surrounded by farms with domestic animals and cultivations of corn. On these communities a strong Jesuit influence was seen, mainly in the surroundings of Matara. This was one of the most important Jesuit populations in that plain forest for its strategic position against the fight of the natives of the Chaco who not only attacked the conquerors but also the sedentary farmers who occupied the riverbanks of the Salado and the Dulce rivers.

In mid- XVI century the two streams which invaded the NOA met, on the one hand Núñez del Prado, coming from Peru and the expedition of Francisco of Aguirre, coming from Chile. Núñez del Prado was commissioned from the Peru to establish a settlement in the region between the the rivers Dulceand Salado, the city of El Barco was founded. In 1553, the captain Francisco de Aguirre arrived to the city and, with the argument of preserving the settlement from the floods, he transferred it to some ten blocks to the north, changing its name to that of Santiago del Estero del Nuevo Maestrazgo. None of the two settlements was enclosed in safe places against the floods. As a consequence, some years later the city should be displaced more toward the west. By means of a Real Identification, in 1563, the counties of Tucumán, Juríes, Diaguitas and Comechingones turned to be governments depending on Lima. Aguirre was replaced by Juan Pérez of Zurita who attempted in vain the foundation of Londres, Cañete and Córdoba of Calchaquí. Due to it Santiago continued being the only stable settlement, and became more important with the return of Aguirre from Peru as a representative from it. With the purpose of opening a route to Asunción, Aguirre explored the coasts of the Salado and the Bermejo rivers. After arriving to the Paraná, he returned along the road by the Tercero river and traveled by the region of the Comechingones. He tried to found a town in the region between the rivers Primero and Segundo, but their men rioted. Then they returned him again to Peru.

While in the XVII century, Santiago belonged to the government of Tucumán, , it covered a territory of 700.000 km2, Santiago did not develop nor expanded to the same rhythm. In 1699, the headquarters of the Bishopric moved to Córdoba and, in 1701, Juan of Zamudio moved the civil government to Salta. In the XVIII century the roads that united Santiago with Santa Fe and Córdoba was blocked due to the continuous attacks of the mocovíes, abipones and tufas, intruding to the Dulce river. The communications with the Peru were cut. When the viceroyship of the Rio de LA Plata was created in 1776, the government of the Tucumán passed to be part of a new structure and, in 1782, Santiago del Estero was lowered in range it was subordinated to Salta. When the Revolution of May took place, Santiago adhered to the fight in favor of the cause, what brought the migration and the renewal of the attacks of the natives. In 1814, the Intendency of Salta was divided in two provinces and Santiago turned to be part of Tucumán. The society santiagueña was divided among autonomists and in favor of the tucumano governor Aráoz. After the balance turned in favor of the autonomy, governor Aráoz tried to recover Santiago with the use of the force but he was defeated.