The performance of a vapor compression refrigeration system (VCRS)-based residential air conditioner operating in a high-ambient temperature (HAT) country was investigated using six zero-ODP (ozone depletion potential) refrigerants as replacements to R22. The non-flammable alternative refrigerants considered in the present research were R134a, R404A, R407C, R410A, R448A, and R507A. Using the basic conservation laws, the VCRS was modeled during steady-state operation and solved using engineering equation solver (EES) software. Coefficient of performance (COP), pressures and temperatures at compressor suction and discharge, Global Warming Potential (GWP), critical pressure and temperature, compressor pressure ratio, volumetric cooling capacity (VCC) specific cooling capacity (SCC), and refrigeration effect were utilized as assessment criteria for the alternative refrigerants considered. From these refrigerants, the highest values of suction pressure, discharge temperature, and condenser pressure were attained by R410A. In addition, the discharge temperatures for all refrigerants, except R134a, were all higher than their corresponding critical values, causing a quicker drop in the VCRS’s performance. As an alternative refrigerant, R407C showed the highest SCC of 141.0 kJ/kg followed directly by 139.2 and 138.0 kJ/kg for R410A and R448A, respectively. A reverse trend was found for VCC with respective values of 4722 and 3775 kJ/m3 for R410A and R448A. Lower volume flow rates and smaller-sized compressors are expected for higher VCC refrigerants. The same trend was found for the compressor’s specific work input and condenser’s specific heat transfer with values of (51.14, 46.82, and 45.38 kJ/kg) and (190.3, 187.8, and 183.4 kJ/kg) for R410A, R407C, and R448A, respectively. For applications in HAT countries, larger condenser’s specific heat transfer makes the refrigerant more applicable. Conversely, with respect to COP, refrigerant R134a with a value of 3.075 was the superior alternative followed by R448A and R407C with respective COPs of 3.042 and 3.011. Based on the overall assessment in terms of environmental obligation, COP, compressor input power, refrigerant flow rate required, and all the evaluations made in this research, refrigerant R448A was recommended as the most appropriate substitute to R22 which can effectively be used in residential air conditioners in a HAT country.