Africa’s modern Zambezi is proposed as an example of a major extant river system, which archives the tectonic events that assembled and then fragmented a supercontinent. The Zambezi and an earlier Karoo river system, (here designated the Proto-Zambezi River system), have a recorded geological history spanning approximately 280 million years. Its original headwaters were formed when the End-Neoproterozoic to Ordovician amalgamation of the Gondwana Supercontinent created a central Himalayan-scale mountain belt, now called the Trans-Gondwana Mountain Range (at the core of the East Africa-Antarctica-Orogenic Belt). Eroded remnants of these mountains were the source of west-directed Dwyka glacial sediments and Ecca and Upper Karoo, Permo-Triassic, rift-controlled lakes and rivers across West Gondwana. The reversed drainage of the Zambezi River started to flow eastwards through the same rift valleys in the Middle Jurassic (at about 165 Ma), as Africa started to separate from the eastern part of West Gondwana, with the resultant development of an eastern seaboard. This second stage in the evolution of the Zambezi River mirrored sequential openings of the Indian and Atlantic Oceans, in the post-Gondwana interplay between epeirogeny and rifting. Protracted longevity of the Zambezi River and its ancient precursor shows that major drainage systems can survive plate break-up, albeit with changed flow directions and continuously evolving catchments.