While seeking a southwest passage to the Indies in 1516, Juan Diaz de Solis discovered the Rio de la Plata (River of Silver). He claimed the surrounding territory (including what is now Argentina) for Spain. Ten years later, Sebastian Cabot became the first to ascend the river, which he named, and to reach the interior.

Pedro de Mendoza, a Spanish noble, established Puerto de Santa Maria del Buen Aire (the original Buenos Aires) in 1536. Plagued by famine and Indian attacks, it was abandoned five years later. Almost 40 years passed before Juan de Garay rebuilt Buenos Aires. The first permanent settlement was Santiago del Estero, founded in 1553. Several settlements in the west and northwest, including Mendoza (1561), San Juan (1562), San Miguel de Tucumn (1565), and Crdoba (1573), were made by expeditions from other Spanish colonies.

For nearly 300 years, Rio de la Plata, as the colony was called, was ruled by Spain. It was under the jurisdiction first of Asuncin (in modern Paraguay) and then of the Vice-royalty of Peru. In 1776 the Viceroyalty of La Plata was created, with Buenos Aires as the capital. This was done to strengthen Spanish control in an area threatened by hostile Indians and Portuguese and British colonizers. Under the viceroyalty, the entire Plata region (present-day Argentina, Paraguay, and Uruguay and the southern third of Bolivia) prospered. Buenos Aires, strategically located on an important river system, became a thriving port.