Availability of water in the Ganges River basin has been recognized as a critical regional issue with a significant impact on drinking water supply, irrigation, as well as on industrial development, and ecosystem services in vast areas of South Asia. In addition, water availability is also strongly linked to energy security in the region. Hence, quantification of spatial availability of water resources is necessary to bolster reliable evaluation of the sustainability of future thermal power plants in the Ganges River basin. This study focuses on the risks facing existing and planned power plants regarding water availability, applying climate change scenarios at the sub-basin and district level up to 2050. For this purpose, this study develops an integrated assessment approach to quantify the water-energy nexus in four selected sub-basins of the Ganges, namely, Chambal, Damodar, Gandak, and Yamuna. The results of simulations using Soil and Water Assessment Tools (SWAT) showed that future water availability will increase significantly in the Chambal, Damodar, and Gandak sub-basins during the wet season, and will negligibly increase in the dry season, except for the Yamuna sub-basin, which is likely to experience a decrease in available water in both wet and dry seasons under the Representative Concentration Pathway (RCP) 8.5 scenario. Changes in the water supply-demand ratio, due to climate change, indicated that water-related risks for future power plants would reduce in the Chambal and Damodar sub-basins, as there would be sufficient water in the future. For 19 out of 23 districts in the Chambal sub-basin, climate change will have a moderate-positive to high-positive impact on reducing the water risk for power plants by 2050. In contrast, existing and future power plants in the Yamuna and Gandak sub-basins will face increasing water risks. The proposed new thermal power installations, particularly in the Gandak sub-basin, are likely to face serious water shortages, which will adversely affect the stability of their operations. These results will stimulate and guide future research work to optimize the water-energy nexus, and will inform development and planning organizations, energy planning organizations, as well as investors, concerning the spatial distribution of water risks for future power plants so that more accurate decisions can be made on the location of future power plants.