The area of the park was inhabited 10,000 years ago by the hunter-gatherers of the Eldoradense culture. They were displaced around 1,000 CE by the Guaraní, who brought new agricultural technologies, and were displaced in turn by the Spanish and Portuguese conquistadores in the 16th century, though their legacy is still alive in this area (the name of the park and the river is Guaraní y guasu, "large water"). The first European to visit the zone was Álvar Núñez Cabeza de Vaca, in 1542; Jesuit missions followed in 1609.

The park was created in 1934 to protect one of the greatest natural beauties of Argentina, the Iguazu Falls, surrounded by the subtropical jungle.

The Iguazú National Reserve was defined by law 18.801 of 7 October 1970 as constituting the western part of the Iguazú National Park. While the national park preserves nature with the least possible alteration, the reserve admits human activities and infrastructure.Creation of the reserve allowed construction of an international airport and alienation of land for three tourist hotels.

Across the Iguazu River lies its Brazilian counterpart (Iguaçu National Park). Both sites were declared World Heritage Sites by UNESCO, in 1984.