The Falkenmark indicator was used to assess vulnerability of the White Volta (106,000 km2) and Pra (20,023 km2) river basins in Ghana to water stress under climate change for the periods 2006–2035 (representing the 2020s) and 2036–2065 (2050s). The indicator is a commonly used measure of water stress and defines thresholds of 1,700, 1,000 and 500 m3/capita/annum as water stress, water scarcity and absolute scarcity, respectively. Downscaled data from ensemble averages of two global climate models, ECHAM4 and CSIRO, were used to drive the Soil and Water Assessment Tool for estimation of basin surface water resources under climate change. The simulated water resources in the two basins showed significant reduction of 22% for 2020. Further reductions were estimated for 2050 (50% and 46% for the White Volta and Pra, respectively). Without climate change, the White Volta basin will attain water stress and water scarcity by 2020 and 2050, respectively; the Pra is already water stressed and expected to worsen to water scarcity by 2020 and absolute scarcity by 2050. Climate change will aggravate the conditions in both basins. Implementation of integrated water resources management and population control measures are recommended for sustainable use and management of water resources in both basins.