Multiphase pumps for offshore plants must perform at high pressure because they are installed on deep-sea floors to pressurize and transfer crude oil in oil wells. As the power for operating pumps should be supplied to deep sea floors using umbilicals, risers, and flow lines (URF), which involve a higher cost to operate pumps, the improvement of pump efficiency is strongly emphasized. In this study, a design optimization to improve the hydrodynamic performance of multiphase pumps for offshore plants was implemented. The design of experiment (DOE) techniques was used for organized design optimization. When DOE was performed, the performance of each test set was evaluated using the verified numerical analysis. In this way, the efficiency of the optimization was improved to save time and cost. The degree to which each design variable affects pump performance was evaluated using fractional factorial design, so that the design variables having a strong effect were selected based on the result. Finally, the optimized model indicating a higher performance level than the base model was generated by design optimization using the response surface method (RSM). How the performance was improved was also analyzed by comparing the internal flow fields of the base model with the optimized model. It was found that the nonuniform flow components observed on the base model were sharply suppressed in the optimized model. In addition, due to the increase of the pressure performance of the optimized model, the volume of air was reduced; therefore, the optimized model showed less energy loss than the base model.