This article explores the impact of inlet pre-swirl on pressure pulsation in a mixed-flow centrifugal pump through a combination of numerical simulations and experimental verification. Firstly, the mixed-flow centrifugal pump’s performance was initially determined through both numerical calculations and experiments. The comparison between them indicated the high accuracy of the numerical method adopted in this paper. Next, the flow pattern within the pump at various inlet pre-swirl angles was carefully compared and analyzed. It was found that positive impulse angle and inlet displacement could lead to circumferential inhomogeneity of the flow field within the impeller, while inlet pre-swirl can significantly counteract the effect of positive impulse angle. The impact of inlet pre-swirl on the flow pattern near the blade inlet will change the intensity of the secondary flow within the impeller passage. Variations in the intensity of the secondary flow can directly affect the strength of the wake and jet in the chamber. Then, the pressure pulsations within the chamber were compared and analyzed for various inlet pre-swirl angles. The results revealed that as the inlet pre-swirl angle increased, the intensity of pressure pulsation decreased significantly. This discovery sheds light on the influence mechanism of inlet pre-swirl on pressure pulsation within mixed-flow pumps, potentially serving as a theoretical foundation for enhancing the operational stability of mixed-flow centrifugal pumps.