Although the R404A indirect refrigeration system (IRS) with an internal heat exchanger (IHX) and R744 as the secondary fluid has potential applications in supermarkets and hypermarkets, the exergy characteristics of this IRS have not been extensively investigated. In this study, the factors affecting the R744 exergy characteristics (degree of subcooling (DSB) and degree of superheating (DSP) of the R404A cycle, DSP of the R744 cycle, condensation temperature (CT) and cascade evaporation temperature (CET), and IHX efficiency) were experimentally evaluated to obtain basic data for the design of R404A IRS with R744 as the optimal secondary fluid. The main results can be summarized as follows: (1) Under given conditions, the smallest change in the system exergy destruction rate (EDR) according to the change in each parameter is the DSP of the R744 cycle (0.3–1%), followed by the DSB of the R404A cycle (6.1–8.8%), the IHX efficiency of the R404A cycle (3.8–14.3%), the DSP of the R404A cycle (11.7–15.9%), the CET (29.4–41.9%), and the CT (35–47%). (2) Also, in terms of the exergy efficiency of system (EES), the largest value was obtained for the DSP of the R404A cycle (2.4–12.7%), followed by the IHX efficiency of the R404A cycle (3–10.2%), the CET (2.2–8.7%), the CT (4–6.9%), the DSB of the R404A cycle (2.7–6.2%), and the DSP of the R744 cycle (0.04–1.2%). (3) In order to lower the system EDR, DSP, DSB, and IHX efficiency of the R404A cycle, the CET must be increased to the maximum, and to lower the DSP of the R744 cycle, the CT must be reduced to the minimum.