When considering the interaction between the impeller and diffuser, it is necessary to provide logical and systematic guidance for their matching optimization. In this study, the goal was to develop a comprehensive matching optimization strategy to optimize the impeller and diffuser of a mixed flow pump. Some useful tools and methods, such as the inverse design method, computational fluid dynamics (CFD), design of experiment, surrogate model, and optimization algorithm, were used. The matching optimization process was divided into two steps. In the first step, only the impeller was optimized. Thereafter, CFD analysis was performed on the optimized impeller to get the circulation and flow field distribution at the outlet of the impeller. In the second step of optimization, the flow field and circulation distribution at the inlet of the diffuser were set to be the same as the optimized impeller outlet. The results show that the matching optimization strategy proposed in this study is effective and can overcome the shortcomings of single-component optimization, thereby further improving the overall optimization effect. Compared with the baseline model, the pump efficiency of the optimized model at 1.2Qdes, 1.0Qdes, and 0.8Qdes is increased by 6.47%, 3.68%, and 0.82%, respectively.