In order to quantify the impact of the Guxian Reservoir’s participation in the joint operation of cascade reservoirs on key and non-key multi-objective benefits, including water supply, power generation, water-sediment regulation and ecology, in the middle-lower Yellow River, two scenarios with and without the Guxian Reservoir in 2030 were set. Based on the theory of multi-objective synergetic optimal operation of cascade reservoirs, the multi-objective synergetic optimal operation model by cascade reservoirs in the middle-lower Yellow River was constructed and solved.The response of multi-objective benefits in the middle-lower Yellow River to the joint operation of the Guxian Reservoir under the background of runoff reduction and comprehensive water demand growth in the future was analyzed. The results show that, compared with the scenario without the Guxian Reservoir, the total synergetic degree of the reservoir system with the Guxian Reservoir operation increased slightly, the order degree of subsystems of water supply and power generation increased,the average annual water shortage in the critical period and non-critical period of agriculture decreased,the average annual power generation of cascade reservoirs increased. In addition to a slight decrease in the frequency of water-sediment regulation, the key and non-key benefits of ecology and water-sediment regulation increased in the scenario with the Guxian Reservoir.