The Madre de Dios River flows into the Beni River in Bolivia, which then turns northward into Brazil, where it joins with the Mamore River to become the Madeira River. The Madeira is a tributary to the Amazon River. The river's main tributaries include the Chivile, Blue, White, Inambari, Tambopata and Colorado rivers.
Mango farming and gold mining are among the many industries on its beaches. Other important industries the river provides are selective logging and farming, both of which are serious environmental problems.
Along the length of the river there are several national parks and reserves, notably Tambopata-Candamo National Park, Manú National Park and Bahuaja-Sonene National Park.