From the confluence the river flows in a generally southwestern direction for about 619 km (385 mi) before encountering the city of Saltos del Guaira, Paraguay.

For approximately the next 200 km (120 mi), the Paraná flows southward and forms a natural boundary between Paraguay and Brazil until the confluence with the Iguazu River.

The massive reservoir formed by the project has been the source of a number of problems for people living along the river, most notably the poorer merchants and residents in the low-lying areas of Encarnación, a major city on the southern border of Paraguay.

River levels rose dramatically upon completion of the dam, flooding out large sections of the city's lower areas.

From the confluence with the Paraguay River, the Paraná again turns to the south for another approximately 820 km (510 mi) through Argentina, making a slow turn back to the east near the city of Rosario for the final stretch of less than 500 km (310 mi) before merging with the Uruguay River to form the Río de la Plata.

This watershed contains a number of large cities, including São Paulo, Buenos Aires, Rosario, Asunción, Brasília, and La Plata.

Some of the species of fish (such as the surubí and the sábalo) are commercially important, and they are exploited for heavy internal consumption or for export.