Abstract The on-board hydrogen fuel cell is a power generation device that converts the chemical energy of hydrogen and oxygen directly into electrical energy. The centrifugal compressor mainly provides oxygen for the cathode of the fuel cell system. With the rapid development of the hydrogen fuel cell industry, the key components of the air compressor field are also developing rapidly. In the technical route, most companies launched two-stage compression centrifugal air compressors in response to the increasing power of the product development trend. The newly developed hydrogen fuel cell system power has reached above 120kW to meet the needs of heavy trucks and other applications. Both the flow rate and pressure ratio of the air compressor are required to increase accordingly. Based on the reduction of parasitic power, the optimal efficiency at the working point of the two-stage centrifugal air compressor is taken as the design goal, from one-dimensional aerodynamic calculation to two-dimensional flow channel design. Finally, the feasibility and accuracy of the aerodynamic design are verified based on key parameters such as pressure ratio, flow rate, and efficiency of the final stage through CFD flow field simulation and test data comparison. The results show that the flow rate is consistent with the calculated flow field, and the maximum error of pressure ratio and efficiency is less than 2%, which meets the target requirements. The research results can provide a research and development basis for designing high-performance centrifugal air compressors for fuel cell vehicles.