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Climate change and human activities are two driving factors that affect the hydrological cycle of watersheds and water resource evolution. As a pivotal input to hydropower stations, changes in runoff processes may reduce the effectiveness of existing operation procedures. Therefore, it is important to analyze the influences of cascade hydropower stations under climate change and human activities and to propose revised optimal operation strategies. For the present study, three runoff series conditions including: Initial runoff, affected by only climate change, and affected by both climate change and human activities are examined by a simulation model to analyze the influence on power generation with four schemes. Additionally, an optimal operation model of cascade power stations is proposed based on the simulation model to generate single and joint optimal operation charts for future hydrological scenarios. The paper also proposes to change human activities based on optimizing operation rules to reduce its influence on downstream power stations. This procedure is theoretically applied and varied for three power stations in the upper Han River, China. The results show that the influence of climate change is greater than that of human activities in that power generation decreased by 17.95% and 12.83%, respectively, whereas combined, there is a reduction of 25.71%. Under existing hydrological conditions, the modified single and joint operation charts would increase power generation by about 32 million and 47 million kWh. Furthermore, after optimizing the upstream project, the abandoned water and power generation of these cascade power stations would reduce by 150 million m(3) and 5 million kWh, respectively. This study has practical significance for the efficient operation of cascade hydropower stations and is helpful for developing reservoir operation theory under changing environments.