The benefits of variable speed centrifugal pumps include high stability, a broad operating range, and adjustable input power. In water distribution systems, the pump units are increasingly using variable speed technology. The energy-saving features and operational stability of the pump station are directly impacted by the hydraulic performance and the operation strategy. In this study, CFD numerical analysis and model tests were adopted to design and evaluate the hydraulic performance of the variable speed centrifugal pump with large flow and wide head variation in Liyuzhou Pump Station. Under the premise of ensuring the wide head variation, the optimized centrifugal pump met the requirements of hump margin and efficiency in the high head zone and the cavitation margin in the low head zone. The test results demonstrated that the operational range of the variable speed centrifugal pump was successfully widened by reasonable hydraulic parameters selection and impeller optimization. The safe and efficient operational range of the variable speed unit was determined by means of taking the performance requirements of the pump’s maximum input shaft power, cavitation characteristics and pressure fluctuation into consideration. The scientific and reasonable operational path to meet the various operation needs was also investigated and determined for the pump station’s actual operation needs. A high efficiency, safe operation, and a simplified control logic were achieved by using the operational path, which makes it a reasonable potential guide for hydraulic design and operational optimization of variable speed centrifugal pumps with large flow and wide head range.