The approach to achieving improved brake thermal efficiency (BTE) for a heavy-duty diesel engine was studied by experiment analysis. The engine was designed on the basis of a two-stage turbocharger system (high-pressure (HP) turbine with variable geometry turbine) and a variable effective compression ratio through retarded intake valve closing timing. The cooperative control of minimum charge density, compressor efficiency, and compressor pressure ratio distribution was proposed to optimize the BTE. The interactive principle was then clarified. Results showed that the gross indicated thermal efficiency (ITEg) increased rapidly with charge density because of the promotion of the mixing rate. However, the increased charge density had a threshold, beyond which the pumping loss (PL) increased rapidly and thus impeded the ITEg growth rate. Therefore, a minimum charge density should correspond to mixing rate requirements. Moreover, the PL decreased with the decrease of the turbocharger driving power when the charge density was kept constant. Therefore, in the case of minimum charge density satisfying the mixing rate, the minimum turbocharger driving power should be limited to minimize PL by improving the compressor efficiency and optimizing the compressor pressure ratio distribution. At the core of the cooperative control of minimum charge density, compressor efficiency, and compressor pressure ratio distribution was thus identified as the simultaneous optimization of the mixing process and the gas exchange process. Such optimization contributed to the maximization of the BTE.