High-speed centrifugal pumps are widely used in several industries due to their high efficiency and small footprint. In actual applications, there are issues such as low operational efficiency and a small high-efficiency flow interval; particularly, the leakage occurring in the impeller channel gap presents a significant barrier to the pump’s performance and stability. This study takes the fully open impeller miniature high-speed centrifugal pump as the object and uses a numerical simulation calculation method. The objective of this research endeavor is to analyze the effects of different flow conditions on a high-speed centrifugal pump’s external characteristics, flow field characteristics, and energy loss. The findings indicate that lobe top clearance exerts a substantial impact on the efficiency of high-speed centrifugal pumps. Increasing the lobe top clearance will result in a reduction in pump head and efficiency, particularly under high flow conditions. The lobe top clearance has a significant impact on the complexity of the flow in the impeller, particularly the flow close to the suction surface of the impeller, according to an analysis of the flow field characteristics. The energy loss analysis further confirms the importance of reducing lobe top clearance for improving pump performance and reducing energy loss. These results provide valuable guidance for optimizing centrifugal pump designs with lobe top clearance.