This paper analyzes the effects of climate change on water availability and use in the Limpopo River Basin of Southern Africa, using a linked modeling system consisting of a semi-distributed global hydrological model and the Water Simulation Module (WSM) of the International Model for Policy Analysis of Agricultural Commodities and Trade (IMPACT). Although the WSM simulates all major water use sectors, the focus of this study is to evaluate the implications of climate change on irrigation water supply in the catchments of the Limpopo River Basin within the four riparian countries: Botswana, Mozambique, South Africa, and Zimbabwe. The analysis found that water resources of the Limpopo River Basin are already stressed under today’s climate conditions. Projected water infrastructure and management interventions are expected to improve the situation by 2050 if current climate conditions continue into the future. However, under the climate change scenarios studied here, water supply availability is expected to worsen considerably by 2050. Assessing hydrological impacts of climate change is crucial given that expansion of irrigated areas has been postulated as a key adaptation strategy for Sub-Saharan Africa. Such expansion will need to take into account future changes in water availability in African river basins.