Several groups populated what is now Argentina at the beginning of the 16th century: Tehuelches, Rehuelches, Rampas, Matacos, Guaycures, Huerpes, Diaguitas, Mapuches,etc. 

When, in the early 16th century, the first Europeans came to Argentina, the Native Americans had already halted the Inca drive southwards from Peru through Bolivia into northern Argentina. The Spaniard Juan de Solís landed on the shores of the Plata estuary in 1516, but the Indians resisted to his conquest intent, he was killed and the expedition failed. Magellan touched at the estuary four years later, but turned southwards to winter on the  Patagonia´s shores, after that he discovered the strait that connects the Atlantic and Pacific oceans.

In 1527 both Sebastian Cabot and his rival Diego García Sailed into the estuary and up the Paraná and Paraguay. They formed a small settlement, Sancti Spiritus, at the junction of the Caraña and Coronda rivers near their confluence with the Paraná, but it was wiped out by the Natives about two years later  and Cabot and García returned to Spain.

Eight years later, in 1536, Pedro de Mendoza, with large force well supplied with equipment and horses, found a settlement called Santa María del Buen Aire what today is the capital city of Argentina. The Natives soon made it too difficult for him; the settlement was abandoned and Mendoza returned home, but not before sending Juan de Ayolas with a small force up the Paraná. Ayolas set off for Peru, already conquered by Pizarro, leaving Irala in charge. It is known for certain what happened to Ayolas, but in 1537 Irala and his men settled at Asunción, in Paraguay, where the Natives where friendly. There were no further expeditions from Spain to colonize what is now called Argentina, and it was not until 1573 that the settlement at Asución sent forces S to establish Santa Fé and not until 11 June 1580 that Juan de Garay refounded the settlement at Buenos Aires. It was only under his successor, Hernando Arias de Saavedra(1592-1614), that the new colony became secure. 

In the meantime there had been successful expeditions into Argentina both from Peru and Chile- the first, from Peru, as early as 1543. These expeditions led, in the latter half of the 16th century, to the foundation at the eastern foot of the Andes of the oldest towns in Argentina: Santiago del Estero, Tucumán, , Córdoba, Salta, La Rioja and San Salvador de Jujuy by Spaniards from Peru following the old Inca road, and San Juan, Mendoza, and San Luis by those from Chile, across the Andes. 

In 1776 the Viceroyalty of Río de la Plata was created-including today's Chile, Paraguay, Argentina, Uruguay and part of Bolivia- with Buenos Aires as its capital. A strong commercial bourgeoisie, based in the port area, was the driving force behind the 1810 revolutionary movement which created the United Provinces of Río de la Plata (Provincias Unidas del Río de la Plata). On 25 May 1810, the cabildo of Buenos Aires deposed the viceroy and announced that it was governing henceforth on behalf of king Fernando VII, the captive of Napoleon. 

Representatives of the various provinces convened at Tucumán in March 1816. On the following July 9 the delegates proclaimed independence from Spanish rule and declared the formation of the United Provinces of South America (later United Provinces of the Río de la Plata). Although a so-called supreme director was appointed to head the new state, the congress was unable to reach agreement on a form of government. Many of the delegates, particularly those from the city and province of Buenos Aires, favored the creation of a constitutional monarchy. This position, which was later modified in favor of a highly centralized republican system, met vigorous opposition from the delegates of the other provinces, who favored a federal system of government. Friction between the two factions mounted steadily, culminating in a civil war in 1819.