The province's first inhabitants were the "chaná-timbúes", the "guaranies" and the "charrúas" They were nomadic, they fed of what they hunted and fished, but slowly they started to practice agriculture. When Santa Fe City was founded in 1573, Juan de Garay took under his protection the other Parana's River band. His followers were the first white residents. The charrúas offered resistance to the Spanish advance. By the middle of the XVIII century they were finally exterminated.

The province's capital city grew round a humble chapel. The first one who called the place "Entre Ríos" in 1783, was colonel Tomás de Rocamora, who was the founder of the cities of Gualeguay, Concepción del Uruguay, and Gualeguaychú. After 1810, Paraná was regarded as a village, and the province started its independence process

In 1814, Artigas' troops defeated the ones from the "Directorio" in Espinillo combat. By that time Entre Ríos Province was created, In 1819, it was under Francisco de Ramirez leadership. The next year it was proclaimed as Entre Rios Republic, including Corrientes and Misiones Provinces. Ramirez died in 1821, and it caused the Republic's crumbling, Lucio Mansilla became Governor. In 1854, Entre Ríos became federal territory, and Paraná City was the seat of the Argentina's Confederation Government. But 4 years later, Entre Ríos federalization came to an end.