This study deals with energy and irreversibility analysis of a cascade refrigeration system employing various refrigerant couples, namely R152a–R23, R290–R23, R507–R23, R234a–R23, R717–R23 and R404a–R23, using a computer code developed for this aim. It is assumed that the refrigeration load is 1 kW, the refrigerated space temperature is −40 °C, and the environment temperature is 300 K, while the degrees of condenser subcooling and evaporator superheat are 5 and 7 °C, respectively, for all cases. Furthermore, the polytropic efficiencies of the compressors are assumed to be equal. It has been determined that the COP of the cascade refrigeration system increases and the irreversibility decreases with rising evaporator temperature and polytropic efficiency for all studied refrigerant couples. On the other hand, the COP of the cascade refrigeration system decreases and the irreversibility increases on increasing the condenser temperature and the difference between the saturation temperatures of the lower and higher temperature systems in the heat exchanger (Δ T). In all cases, the refrigerant couple R717–R23 has the highest COP and lowest irreversibility except for the limited ranges of polytropic efficiency (50–60%) and Δ T (13 K–16 K), while R507–R23 has the lowest COP and highest irreversibility. The refrigerant couple R152a–R23 has been found to be an alternative couple to R717–R23 for the above mentioned ranges of polytropic efficiency and Δ T. The refrigerant couples R134a–R23 and R290–R23 have placed in the middle range, and R404a–R23 can be considered as a replacement couple for R507–R23 in all cases.