The permanent settlement of today's Rosario area began of the 17th century. There was no clear foundation date. The first landowner was Captain Luis Romero de Pineda, and the first formal colonial settlement was initiated by Santiago de Montenegro, who was appointed Mayor in 1751.

On 27 February 1812, General Manuel Belgrano raised the newly created Argentine flag on the shores of the Paraná, for the first time.

Until the 1850s Rosario was a small village of 3,000 inhabitants, with its port banned from foreign trade by an 1841 decree of Juan Manuel de Rosas. On 5 August 1852 Rosario was declared a city after a request by Justo José de Urquiza, who also opened up international trade. By 1880, Rosario had become the first export outlet of Argentina; in 1887 it had about 50,000 inhabitants. It was even declared the federal capital in three occasions, but each time it was vetoed by the Executive Branch.

In 1946 Rosario massively supported Juan Perón's rise to power. The city received the benefits of the nationalization and subsidizing of many industries. Perón was deposed in 1955. In 1969 workers and students took the streets to protest against the dictatorship (Rosariazo). During the dictatorship started in 1976, hundreds of citizens were "disappeared" by the government. The city hosted some matches of the Football World Cup 1978.