The Santarém region has been a hub of human settlement for many thousands of years; some of the oldest remains of human settlement were discovered in Monte Alegre a short distance downstream. A Jesuit mission was established at the meeting of the Tapajós and Amazon rivers in 1661, and officially named Santarém in 1758.

The later history of Santarém was marked by the rubber boom and bust, and a series of gold rushes that started in the 1950s. The economy today is based mainly on soy and hardwoods and, increasingly, on gold and bauxite mining, whose severe environmental impact make them controversial.