Supercritical carbon dioxide (SCO 2 ) is a vital working fluid in the application of power units and its high density helps to achieve a compact mechanical structure. Centrifugal compressors are of vital use in various kinds of equipment. In this paper, a SCO 2 centrifugal compressor of large input power and mass flow rate is designed and numerically investigated. A thorough numerical analysis of the unsteady flow field in the centrifugal compressor is performed in ANSYS-CFX. The computation adopts hexahedral mesh, finite volume method, and the RNG k-ε two-equation turbulence model. Streamlines, temperature, pressure, and Mach number distributions at different time steps in one revolution period are covered to present the unsteady effect of turbomachinery. Meanwhile, the force on a single rotor blade is monitored to investigate the frequency components of exciting force, thus providing the foundation for vibration analysis. Moreover, the torque, output power, pressure ratio, and isentropic efficiency in the steady and the unsteady time-averaged condition are calculated and compared with the design condition to measure the validity of the design. In summary, the unsteady computation result reveals that the unsteady flow characteristics are prominent in the designed compressor and the design of impeller and diffuser meet the requirement.