Effective evaluation indicator is the focus of air compressor structural optimization and development of control strategies, leaving to be further investigated from physical occurrence mechanism. Considering air expansion and compression, on the basis of coupling computational fluid dynamics (CFD) with classical irreversible thermodynamics (CIT), an extended entropy generation rate was established. Accordingly, various entropy generation rates for air compressor under wide operating conditions was investigated, aiming to what, where and how much the energy was dissipated. Results show that entropy generation rate related to air expansion and compression is always the largest contributor to the total entropy generation of the system under all operating conditions. A new dimensionless number R is defined to distinguish the fluid-related entropy generation rate and mechanical-related entropy generation rate. Furthermore, physical-based empirical models concerning the relationship of entropy generation rates, motor speeds and loads are proposed in this study, whose usage for guiding structural design was discussed. The work done in this paper can not only provide a new method for guiding the structural design of air compressors, but also providing a new idea for air compressor-fuel cell system’s optimal control.