For current and future sustainability, refrigerants with high global warming potential (GWP) are being phased out and replaced with environmentally friendly refrigerants. To this end, research into the current and possible future low-GWP refrigerant alternatives in cascade refrigeration systems has caught much attention. In this paper, a mathematical model is developed to assess the optimum energetic, exergetic, and operational parameters of a cascade refrigeration system using water as a refrigerant in the upper cycle with R744, N2O, R41, R717, R290, and R1270 in the lower cycle for a cooling load of 10 TR (35.2 kW). Multiple studies have been conducted for evaporator temperatures between −25 and 5 °C. Results show that R41 and R717 as low- and intermediate-temperature refrigerants, respectively, are recommended for the bottom cycle. Furthermore, R717-water showed improved coefficient of performance (COP) compared to other top cycle refrigerants, with a COP improvement of 2.9% to 8.6%. This study demonstrates the thermal feasibility of using water as a refrigerant in low-temperature cascade systems. Using water as a refrigerant in the top cycle showed promising results in low-temperature applications without the risk of solidification. However, the drawbacks are the high volumetric flowrate and compressor discharge temperature, requiring high capacity water injected compressor.