Modelling uncertainty under future climate change and socio-economic development is essential for adaptive planning and sustainable management of water resources. This is the first study in South Africa incorporating uncertainty within climate and development scenario modelling for understanding the implications on water availability through comparison of the resulting uncertainty. A Water Evaluation and Planning model application was developed for the Amatole system (South Africa), which consists of three catchments with inter-basin transfers. Outputs for three sets of scenarios are presented, namely development-only, climate-change-only and climate-and-development scenarios. Near future (2046–2065) development uncertainty was estimated from three scenarios (lower, intermediate and upper) and climate change uncertainty from nine downscaled global climate models under the A2 emissions scenario. Consideration of development increased the uncertainty associated with climate-change-only scenarios, particularly at low flows. Water deficits are projected in the future for the Amatole system as the present water infrastructure cannot meet water demands under the near future intermediate and upper development scenarios. The deficits are likely to be exacerbated by inclusion of environmental flows (not included in the model). The recommended strategy is that of adaptive management, in combination with continual monitoring of climate and development changes, for reducing future uncertainty.