The Makgadikgadi Pans in northern Botswana are the desiccated relicts of a former major inland lake system, with fossil shorelines preserved at five distinct elevations (~995 m, 945 m, 936 m, 920 m and 912 m). These lakes persisted in the Makgadikgadi Basin, which evolved in the Okavango-Makgadikgadi Rift Zone: the south-western extension of the East African Rift System (EARS) into northern Botswana. This paper synthesizes cross-disciplinary evidence, which reveals that the antiquity of this lake complex has been widely underestimated. It presents a Regional Drainage Evolution Model that invokes tectonically initiated drainage reorganizations as the underlying control over lake evolution. Lake formation was initiated by rift-flank uplift along the Chobe Fault, across the course of the Zambezi River, which diverted the regional drainage net into the Makgadikgadi Basin. Filling of the basin initiated a major climatic feedback mechanism that locally increased rainfall and lowered evaporation rates. This progressively enhanced water input to the basin, and most likely led to overtopping of the Chobe Horst barrier during the three highest lake stands, with outflow into the Zambezi River. During this period, the hydrology of the basin would have been closely analogous to modern, shallow Lake Victoria. Fragmentation of the regional drainage network by successive river captures resulted in sequential contractions of the lake to lower elevation shorelines. In turn, resultant decreases in areas of these successive lakes modulated the magnitude of the feedback mechanism. Thus, loss of the Upper Chambeshi catchment caused the lake to drop from the 990 to the 945 m level. Severance of the former link between the Kafue and Zambezi resulted in a further drop to the 936 m shoreline. Inflow declined further after the impoundment of a major lake (Palaeo-Lake Bulozi) on the Upper Zambezi River, causing contraction to the 920 m shoreline. Continued incision of the Zambezi channel into the Chobe horst barrier ultimately terminated input from this river to the Makgadikgadi depression, causing contraction of the lake below 920 m, sustained by the Cuando and Okavango prior to final desiccation. This Regional Drainage Evolution Model contradicts previous proposals that have invoked Late Pleistocene climatic forcing to explain inferred fluctuations in lake levels. The timeframe developed for the drainage reorganizations requires that the lake was initiated by ~1.40 to 0.51 Ma at the most recent (Early – Mid-Pleistocene), while archaeological evidence shows that it had contracted below the 936 m shoreline before 500 ka. This contrasts with 14C and quartz luminescence dates (generally <100 ka), which require that the 945 m lake stage was extant during much of the Upper Pleistocene. The calcareous radiocarbon dates reflect multiple episodes of calcrete formation, while the young luminescence dates are ascribed to the extensive bioturbation of older Kalahari landforms.