Centrifugal pumps are widely used in industrial production, agricultural irrigation, water transportation, energy storage pump station and ocean engineering, and the development prospect of centrifugal pump is to work in a wide operation region with high efficiency. In this work, the achievement of high-efficiency operation for multiple conditions in a wide operation region is strenuously realized by a new design method from the perspective of flow mechanism analysis and theoretical derivation. A new dimensionless slip-diffusion parameter Φ on consideration of the slip effect and diffusion effect in impeller is proposed. On the basis of the new parameter Φ, a new design method of centrifugal pump is established to improve the pump efficiency for multiple conditions in a wide region. Two centrifugal pumps with different specific speeds of 102 and 127 are designed to validate the proposed design method. When the slip-diffusion parameter Φ ≈ 0.677, the centrifugal pump can achieve the maximum average efficiency for multiple conditions. For Φ < 0.677, the pump efficiency rapidly drops at the high flow rate region. For Φ > 0.677, the pump efficiency rapidly drops at the low flow rate region. Two centrifugal pumps are numerically simulated to obtain the flow pattern, and the entropy production method is used to analyze the relationship between flow field and energy performance of the pumps. Entropy production mainly appears at the blade suction side and the impeller outlet. For different flow rates, the total entropy productions of pumps with Φ ≈ 0.677 are always the minimum.