The ongoing cascading hydropower exploitation in southwestern China has been the subject of debate and conflict in recent years. This study aims to assess the climate change impacts on the hydropower system of Yuan River and to quantify the future potential in operation optimization of Gasa-Madushan (GS-MDS) Reservoir system. The Community Climate System Model version 4 (CCSM4) projections are bias-corrected and downscaled to drive the Soil Water Assessment Tool hydrological model, aiming to predict the climate and runoff changes for the future. Then, an adaptive operation chart model of cascaded reservoirs is established to balance hydropower generation and ecological requirements under climate change. In the future, the decadal average temperature and annual average precipitation will possibly increase by 0.80–2.22 °C and 2.56–4.65%, respectively; the monthly average runoff may increase by 6.89%, 6.17%, and 18.26% for GS Reservoir Basin, and by 8.89%, 8.14%, and 23.14% for MDS Reservoir Basin under Representative Concentration Pathways 2.6, 4.5, and 8.5, respectively. The adaptive operation chart results in a reduction of 52.66–70.77% in the total water shortage at a cost of 2.09–4.54% decrease in total power generation of the GS-MDS cascaded hydropower system compared to that of non-adaptive operation chart.