Climate change impacts may influence hydropower generation, especially with the intensification of extreme events and growing demand. In this study, we analyzed future hydroelectric generation using a set of scenarios considering both climate change and consumptive demands in the São Francisco River Basin. This project will increase consumptive demands for the coming decades. Five models from the recently released Coupled Model Intercomparison Project Phase 6 and two scenarios, SSP2-4.5 and SSP5-8.5, were considered to estimate climate change projections. The affluent natural flows, regulated flows, and the hydroelectric energy generated were estimated for four multi-purpose reservoirs considering all existing and new demands. The conjunction of scenarios indicated a possible significant reduction in water availability, increased consumptive demands, especially for irrigation, and reduced power generation. Only at the Sobradinho hydroelectric plant, the decrease ranged from −30% to −50% for the period 2021 to 2050 compared to the historical period (1901 to 2000). The results can provide insights into future energy generation and water resources management in the basin.