The Madre de Dios River, homonymous to the Peruvian region it runs through, then becomes the Beni River in Bolivia and then turns northward into Brazil, where it is called the Madeira River. The Madeira is a tributary to the Amazon River.

The Alto(Upper) Madre de Dios, where the road from Cuzco ends at the riverside town of Atalaya. It is here that the Andes end and the river becomes navigable.

The Madre de Dios is an important waterway for the department of Madre de Dios, particularly Puerto Maldonado, the largest town in the area, and the capital of the department. Gold mining is the main industry on its beaches, which is a major environmental problem due to the use of mercury in the extraction of the gold dust. Other important industries the Madre de Dios 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, Manu National Park (also known as Manu Biosphere Reserve) and Bahuaja-Sonene Reserved Area.

The Madre de Dios serves as the largest watershed in the area, as part of the vast Amazon River's watershed.