Wall roughness in centrifugal pump side chambers significantly affects flow behavior and overall pump performance, yet current research in this area is limited. This study investigates the effects of rough rotor, rough stator, and rough rotor–stator on side chamber flow using numerical simulations and experimental validation. A simplified model is proposed to reduce computational costs, and its accuracy is verified by comparison with a typical centrifugal pump. Using the entropy generation method, the local energy loss and macroscopic fluctuations due to roughness are analyzed. The results show that the effect of rotor roughness plays a dominant role, while the effect of stator face roughness is relatively small. The roughness of the pump chamber walls leads to an increase in centrifugal pump head and a decrease in efficiency. The maximum increase in the centrifugal pump head reaches 1.66% and the maximum decrease in efficiency reaches 1.51% in the studied range. These findings indicate that wall roughness is a key factor in flow losses and potential system instability, with the simplified model offering quick and accurate predictions.