Combined with the characteristics of multi-stage submersible pump, the pump with sloping impeller and space guide vane was optimized using efficiency as optimization object. To improve the accuracy of numerical simulation, parametric fitting for sloping impeller and space guide vane was carried out. In the process of optimization, the blade inlet and outlet angle of the impeller and guide vane were considered as the control parameters. The range of angle was increased ±20°compared with the original model. Based on the successive flow field check, the optimal impeller model was obtained in the variation range of control parameters searching the optimum value of objective function based on genetic algorithm. The optimal model was obtained when inlet angle at the bottom of the blade was 35.53° and the outlet angle was 27.32°, the inlet angle of the guide vane was 15.48° and outlet angle was 61.75°. The pump efficiency increased by 4.12%, and the single stage head increased 1.449m. The range of high efficiency has been extended, the stability of pump operation is improved, and the performance of the pump is optimized.