The two-level serial solution strategy is established for the Moon-Earth return mission of manned spacecraft based on hybrid optimization algorithm. First, the initial trajectory is obtained by adopting hybrid optimization algorithm consisting of differential evolution method and sequence quadratic method under the improved double two-body model. Then the sequence quadratic method is applied to obtain the final trajectory under the high precise dynamic model. The effectiveness and reliability of the approach proposed are demonstrated by the simulation tests, and the high precision and excellent convergence of the proposed method are indicated. Finally, according to a great deal of simulation results by the method, the trajectory characteristics such as the reachable set and velocity change are analyzed.