This study numerically investigated a highly loaded centrifugal compressor stage with various tandem-designed impellers and a wedge diffuser using a state-of-the-art multi-block flow solver to better understand the fundamental mechanism of tandem impellers. The flow topologies in the impeller are analyzed in detail to identify the underlying physical mechanism of the effect of the tandem-impeller design on the performance of the compressor stage. Particular emphasis is placed on the evolution of the flow structure in the tandem bladed impeller by varying the inducer–exducer clocking arrangements. The results demonstrate that a tandem compressor design is more efficient than a conventional compressor design for the majority of the tested clocking configurations, and the tandem clocking friction significantly affects the impeller performance. For the tested centrifugal compressor stage, an approximately 1.4% increase in isentropic efficiency and 1.3% increase in stall margin are achieved with an inducer–exducer clocking fraction of 25%. The improvement in the primary centrifugal compressor stage performance by the tandem-impeller design is a result of the manipulation of the flow structure and the reduction in the highly distorted jet/wake exit flow pattern. Compared to the conventional impeller designs, the tandem-impeller clocking arrangement variation significantly affects the high-momentum flow along the exducer suction surface and inducer wake diffusion, inlet axial velocity, and flow angle of the exducer blade. Therefore, this variation is advantageous for shortening the length of the boundary layers on both parts of the blade and enables an intense mixing at the exducer passage to improve the flow uniformity of the impeller exit. As a result, the impeller efficiency, diffuser recovery, and stalling margin can be improved compared with the conventional design.