In response to the practical problem of insufficient consideration of the impact of multi stakeholder game relationships on reservoir operation decisions in the traditional centralized multi-objective optimization paradigm, which makes it difficult to guarantee the ecological flow of rivers, two scenarios of joint guarantee and individual guarantee ecological flow were set up. A leader-follower game optimal operation model for cascade reservoirs under the principle of power generation obeying flood control scheduling was established, and a case study was conducted on Pangduo-Zhikong cascade reservoirs in the Lhasa River Basin. The results indicate that cascade reservoirs have the optimal comprehensive benefits under the joint guarantee of ecological flow. It is difficult to highlight the operation benefits under the ecological flow guaranteed by the Zhikong Reservoir alone, in which the flood control benefits are reduced by 4.35%, and the power generation benefits are reduced by 1.66%. The main reason for the decrease in benefits is that under the single reservoir guarantee mode, the Pangduo Reservoir tends to retain water and reduce discharge during the dry season, which leads to the excessive decline in the water level of the Zhikong Reservoir to ensure the ecological flow.