It has a length of approximately 960 kilometres and a catchment area of 367,201 km2 with Botswana, Namibia and South Africa sharing roughly about a third of the basin each.

In its middle course the Molopo River forms a significant section of the border between Botswana and South Africa.

Floods are rare because the vast sandveld areas of the Kalahari Desert on the Namibian side of its basin absorb all water from the seasonal rains.

In case of exceptionally heavy and continuous precipitation the flow discharges into the Orange River, which it meets downstream of Augrabies Falls National Park at 28°31′02″S 20°12′46″E / 28.51722°S 20.21278°E / -28.51722; 20.21278.

The main tributary of the Molopo is the Nossob, whose confluence is some 50 km south of Twee Rivieren, at 890 metres or 2,920 feet above sea level.