<p>To reduce secondary-flow intensity and improve the aerodynamic performance of a centrifugal compressor, this study investigates the influence of overall loading distributions and local loading control coefficients, coupled with dimensionless circulation coefficient and axial velocity, on impeller aerodynamic performance. A three-dimensional inverse-design methodology is employed to design a CO₂ centrifugal compressor with a medium flow coefficient. The Computational Fluid Dynamics (CFD) results indicate that applying a global loading distribution pattern with rear-loading on the hub side and front-loading on the shroud side, while locally increasing the loading near the hub leading edge and decreasing it near the trailing edge is able to reduce the region of low velocity at the blade outlet and weaken the secondary flow intensity within the passage and on the blade surfaces. Subsequently the overall aerodynamic performance of the newly designed centrifugal impeller is improved compared to the prototype. To validate the universality of this loading distribution strategy, the same principle is applied to redesign the Eckardt’s impeller with medium flow coefficient. The CFD results confirm the improved aerodynamic performance for the modified impeller, suggesting that the proposed loading distribution law exhibits general applicability for medium-flow-coefficient impellers.</p>