The story begins with an older, unofficial settlement called Arroyo de China, recorded around 1778 on a creek at what is now the city's southern edge, where the first chapel rose at a site later used as a cemetery. The formal founding came on 25 June 1783, when Tomás de Rocamora, acting on the viceroy's commission, established the town under the resonant name Our Lady of the Immaculate Conception of Uruguay. Rocamora pulled the population north to what became the administrative and commercial heart of the city. Even the full name has been argued over for two centuries, some insisting it was always simply Concepción del Uruguay.

In 1814 the Supreme Director Gervasio Antonio Posadas named Concepción del Uruguay the capital of the newly created province of Entre Ríos. The following year it hosted something larger. On 29 June 1815, José Gervasio Artigas convened the Congress of Oriente, the assembly of the Free Peoples, here. Historians consider it the first declaration of independence in the Río de la Plata, preceding the Congress of Tucumán by a year. In 1820 General Francisco Ramírez went further still, proclaiming the Republic of Entre Ríos with Concepción as its capital, a sovereign experiment that dissolved when Ramírez died the next year.

The city's largest moment came in 1851. At the foot of the pyramid in its central plaza, Justo José de Urquiza issued his pronouncement against Juan Manuel de Rosas, the strongman who had ruled Argentina with an iron hand. That declaration set in motion the campaign that ended at the Battle of Caseros on 3 February 1852, where Urquiza prevailed and cleared the way for the National Constitution adopted the following year. Two years earlier, in 1849, Urquiza had also founded here the Colegio del Uruguay, the first secular secondary school in the country, the classroom that would produce a string of Argentine and Paraguayan presidents.

There is a charming problem of identity here. Because the river and the country next door share the name Uruguay, the people of Concepción del Uruguay are called uruguayenses, while citizens of the neighboring nation are uruguayos, a small linguistic fence to keep the two from being confused. The capital eventually moved to Paraná in 1883, but the city kept working. Today it anchors a region that, with nearby Gualeguay and Colón, accounts for the great majority of Argentina's chicken exports, and it has grown into the largest educational center in the area, home to several universities and the Palacio San José, Urquiza's grand residence, just outside town.