Centrifugal pumps are often used for pumping liquids from one priority area to another, which require working effectively in terms of performance and reliability. The objective of this study is to enhance the hydraulic performance and reliability of a centrifugal pump based on computational fluid dynamics (CFD) optimization. The shapes of the expeller vane and volute tongue were optimized based on the following six design parameters; outer diameter, exit angle, front and rear heights, back sidewall gap, and tongue angle. The hydraulic efficiency and axial thrust were chosen as the optimization objectives. In this sense, a design of experiment (DOE) technique was utilized to generate 45 design samples. A response surface modeling (RSM) approach was employed to investigate the interaction between the parameters and objectives. The accuracy of the numerical simulation was verified by the experimental data and showed a good agreement. The optimization was found to improve the hydraulic efficiency by 2.92%, whereas the axial thrust was decreased by 7.51%.