Simulation-optimization methods are often used to derive operation rules for large-scale hydropower reservoir systems. The solution of the simulation-optimization models is complex and time-consuming, for many interconnected variables need to be optimized, and the objective functions need to be computed through simulation in many periods. Since global solutions are seldom obtained, the initial solutions are important to the solution quality. In this paper, a two-stage method is proposed to derive operation rules for large-scale hydropower systems. In the first stage, the optimal operation model is simplified and solved using sampling stochastic dynamic programming (SSDP). In the second stage, the optimal operation model is solved by using a genetic algorithm, taking the SSDP solution as an individual in the initial population. The proposed method is applied to a hydropower system in Southwest China, composed of cascaded reservoir systems of Hongshui River, Lancang River, and Wu River. The numerical result shows that the two-stage method can significantly improve the solution in an acceptable solution time.