Thermodynamic analysis was conducted, in detail, to compare the performance of an air conditioning system with and without an air-membrane heat and mass exchanger. The study evaluated the performance of the system considering four promising new refrigerants: R1234yf, R1234ze, R32, and R423A. To evaluate the performance of the system, key performance parameters were used, including, coefficient of performance (COP), exergy destruction rate, second law efficiency, compressor work, irreversibility ratio, fuel depletion ratio, and productivity lack. In addition, the effect of varying the compressor pressure ratio, effectiveness of the membrane, and the relative humidity of fresh air on the performance of the system were evaluated for both configurations. The performance of an air conditioning system significantly improves when an air-membrane heat and mass exchanger is used. The main reason of this improvement is the significant drop in the cooling load and, consequently, the compressor input power. Furthermore, the study showed that COP as a measure of performance is not enough to have an appropriate comparison for the performance and further detailed analysis is needed, such as exergy analysis. Therefore, exergy analysis was also conducted to fully assess the advantages of using a membrane with an air conditioning system. From thermodynamics point of view, the study showed that R1234ze has the best performance while R32 has the lowest performance.