The cascade refrigeration systems (CRS) used in hypermarkets and supermarkets, which are used by many people, have been employing R744 for the low-temperature cycle (LTC) and R404A for the high-temperature cycle (HTC) due to environmental and public safety issues. However, the use of R404A is limited due to its high GWP, and therefore research on alternative refrigerants is necessary. Nevertheless, there is no detailed study in the literature that compares and analyzes the three refrigerants for practical design by applying R744 for LTC and R404A, R448A, and R449A for HTC in CRS. Therefore, this study aims to provide data for the practical detailed design of an alternative system to R744/R404A CRS. Under standard conditions, we analyzed how the exergy destruction rate (EDR) and exergy efficiency (EE) of the system and the EDR of each component change when the important factors affecting CRS (degree of superheating (DSH), degree of subcooling (DSC), and internal heat exchanger (IHX) efficiency of HTC, DSH of LTC, condensation temperature (CT), evaporation temperature (ET), cascade evaporation temperature (CET), and temperature difference of CHX) are varied over a wide range. The main conclusions are as follows. (1) Under the given constant conditions, the smallest change in system EDR based on R448A is DSH of HTC (decreased by 0.07–0.1 kW), followed by IHX of HTC (decreased by 0.12–0.3 kW), DSH of LTC (increased by 0.19–0.25 kW), DSC of HTC (decreased by 0.59–0.69 kW), temperature difference of CHX (increased by 1.57–1.83 kW), CET (decreased and then increased by 0.67–4.43 kW), CT (increased by 1.49–3.9 kW), ET (decreased by 2.39–4.61 kW). (2) The highest change rate of system EE based on R448A is CET (increased and then decreased by 1.38–8.28%), followed by temperature difference of CHX (decreased by 2.96–3.16%), ET (increased and then decreased by 0.63–2.75%), DSC of HTC (increased by 1.26–1.34%), CT (increased and then decreased by 0.24–1.12%), IHX of HTC (increased by 0.11–1.02%), DSH of LTC (decreased by 0.35–0.49%), and DSH of HTC (increased by 0.14–0.19%).
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