To improve the transport performance of a rotodynamic multiphase pump for a gas–liquid mixture, we took the head and efficiency index at rated flow rate with 15% inlet gas volume fraction as the indices, and used the orthogonal test design method and CFD technology to optimize. We selected the blade shroud angles at the leading edge and trailing edge, and axial length of the impeller, as well as the inlet incidence angle and blade number of the diffuser, and a total of five factors were used for the orthogonal test. The weight function was used to determine the final trial protocol. The results showed that the blade shroud angle at the trailing edge had the greatest influence on the head and efficiency indices. Under the rated flow rate with a 15% inlet gas volume fraction, the head and efficiency of the optimized pump were increased by 2.81 m and 5.6%, respectively, in comparison to the base pump. After the optimization, the partial fast-speed regions at the inlet of the impeller passage and the partial low-pressure regions on the blade suction side of the impeller disappeared, the accumulation of the gas phase on the blade suction side at the impeller outlet was suppressed, and the pumping performance of the impeller using the gas–liquid mixture was improved greatly. This study provides an important theoretical basis for the optimization and design of a multiphase pump.