Increasing water demand due to population growth, economic expansion and the need for development puts a strain on the supply capacity of the Vaal River catchment in South Africa. Climate change presents additional challenges in the catchment which supports the country's economic hub, more than 30% of its population and over 70% of its maize production. This study evaluates the influence of climate change on current and future intra-annual water availability and demand using a multi-tiered approach where climate scenarios, hydrological modelling and socio-economic considerations were applied. Results shows exacerbated water supply challenges for the future. Temperature increases of between 0.07 and 5 °C and precipitation reductions ranging from 0.4 to 30% for Representative Concentration Pathways (RCPs) 4.5 and 8.5, respectively, are also predicted by the end of the century. The highest monthly average streamflow reductions (8–10%) are predicted for the summer months beyond 2040. Water Evaluation and Planning (WEAP) simulations project an increase in future water requirements, gaps in future water assurance and highlight limitations in existing management strategies. The study recommends a combination of adaptation plans, climatic/non-climatic stressor monitoring, wastewater-reuse, conservation, demand management and inter-basin transfers to reduce future uncertainty in monthly water sustainability.