The spanwise distribution of impeller exit circulation (SDIEC) has a significant effect on the impeller performance, therefore, there is a need for its consideration in the optimization design of mixed-flow pumps. In this study, a combination optimization system, including a 3D inverse design method (IDM), computational fluid dynamics (CFD), Latin hypercube sampling (LHS) method, response surface model (RSM), and non-dominated sorting genetic algorithm (NSGA-Ⅱ) was used to improve the performance of the mixed-flow pump after considering the effect of SDIEC on the performance of the impeller. The CFD results confirm the accuracy and credibility of the optimization results because of the good agreement the CFD results established with the experimental measurements. Compared with the original impeller, the pump efficiency of the preferred impeller at 0.8Qdes, 1.0Qdes, and 1.2Qdes improved by 0.63%, 3.39%, and 3.77% respectively. The low-pressure region on the blade surface reduced by 96.92% while the pump head difference was less than 1.84% at the design point. In addition, a comparison of the flow field of the preferred impeller and the original impeller revealed the effect of SDIEC on mixed-flow pump performance improvement and flow mechanism.