In order to improve the operation performance of the multi-stage double-suction centrifugal pump and reduce the internal energy loss of the pump, this paper proposes a single-objective optimization design method based on non-hierarchical response surface model (RSM) and the multi-island genetic algorithm (MIGA). Nine parameters, such as the blade outlet width and blade wrap angle, were used as design variables, and the optimization objective was the efficiency under design conditions. In total, 149 sets of valid data were obtained under the latin hypercube sampling method (LHS), the corresponding thresholds were set for efficiency and head, and 99 sets of valid data were obtained. A cross-validation analysis of the sieved data was carried out based on non-hierarchical RSM, global optimization of the efficiency was carried out using MIGA, and numerical verification was carried out via CFD. The research results show that compared with hierarchical RSM, non-hierarchical RSM can approximate the nonlinear relationship between the objective function and the design variables with higher accuracy, and the model fitting R2 value was 0.919. The efficiency was improved by 3.717% after optimization. The overall prewhirl of the impeller inlet after optimization decreased, the internal speed of the volute significantly improved, the large-area vortex at the volute and the outlet pipe was eliminated, the impact loss at the volute separating tongue disappeared, and the overall hydraulic performance of the pump was improved. The total entropy output value of the optimized pump was reduced by 4.79 (W/K), mainly concentrated in the reduction in the entropy output value of the double volute, and the overall energy dissipation of the pump was reduced.