In 1536, the Spaniard Pedro de Mendoza—under orders by the Spanish kingdom to establish a settlement—and 1,600 of his men camped on a bluff overlooking the Río de la Plata. Relations with the local indigenous people quickly deteriorated, and the Spaniards were forced to leave five years later. In 1580, Juan de Garay (c. 1528–1583) and 300 people settled at the mouth of the Río Riachuelo and reestablished the city of Buenos Aires.

For 200 years, Buenos Aires remained a sleepy, isolated town, governed by the Viceroyalty of Peru. Buenos Aires' growth was hampered by Spain's rigid trade regulations, which allowed only certain ports to handle goods destined for Spain. Any goods from Argentina traveled over vast distances by land to the Peruvian port of Callao, where they were shipped to Panama and then transferred to ships going to Spain.

By the early eighteenth century, the fertile and well-irrigated land west and north of Buenos Aires was producing thousands of tons of cereal and dried beef and thousands of cattle hides. Smugglers exported the goods through the Port of Buenos Aires to markets in Brazil and the Caribbean Islands, much to the consternation of Spain, which could not stop the illegal trade. In 1776, the Spanish kingdom named Buenos Aires the capital of the new Viceroyalty of the Río de la Plata.

British troops attempted to invade the city in 1806 and 1807 but were soundly defeated by local forces. Already infused with a strong sense of self-identity, the victories over the British boosted Argentine nationalism among Porteños. By 1808, when French commander Napoleon Bonaparte's forces invaded Spain, the citizens of Buenos Aires began to question their allegiance to the Spanish kingdom. Two years later, in May of 1810, Buenos Aires severed its ties with Spain. But the surrounding provinces did not follow suit until 1816, when they declared their independence and named Buenos Aires the new capital of the United Provinces of Río de la Plata.

Early independence in Argentina was marked by an often bitter struggle between two political groups: the Unitarists and the Federalists. The Unitarists wanted a strong central government, while the Federalists wanted local control.

By the late 1880s, Buenos Aires was becoming one of the wealthiest and most important cities in the world. Porteños began to call their city the Paris of South America and embarked on an ambitious construction program. Beautiful mansions and buildings, wide avenues, expensive hotels, and restaurants became permanent fixtures in the city's landscape. The Teatro Colón, an architectural jewel used for ballet, opera, and classical music, opened in 1908 to world acclaim.

Argentine railroad construction in the second half of the 19th cent. stimulated settlement and cultivation of the pampas, whose products Buenos Aires marketed and exported. The city's spectacular economic development attracted immigrants from all over the world through the 1920s. Shantytowns built on the city's margins remained through the 1950s. The development of the city's transportation system in the 1970s and 80s facilitated economic growth.

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