Safety and reliable operation is one of the most important research areas for centrifugal pump systems, due to the interaction of complex flow, large structural load, and vibration caused by the operation of the impeller. To analyze the internal flow and impeller deformation of the centrifugal pump, the single-stage single-suction centrifugal pump titled IS100-80-160 was selected as the research object. Under the principle of single variable, the turbulent flow and structural response of three impellers designed by different parameters were calculated by CFX and ANSYS Workbench. A numerical simulation of steady flow at different flow rates of the centrifugal pump was carried out, and its hydraulic performance is consistent with the corresponding experimental results. By comparing the deformation of the impeller rotor system, it was found that the closed impeller has the worst stability with the best hydraulic performance; the impeller with split blades has the worst stability with the best hydraulic performance. This study could enhance the understanding of impeller FSI on centrifugal pump stability and provide a reference for improving the operational stability of centrifugal pumps.