The popularity of vehicles and the increased time spent in cars with air conditioning systems has led to regulations in many countries that require the use of environmentally friendly refrigerants with minimal global warming and zero ozone depletion potential (GWP and ODP). Cars need high-performance, eco-friendly air conditioning systems to reduce their impact on the environment, lower fuel consumption, and decrease carbon emissions. The aim of the current work was to propose CO2-based blend zeotropic refrigerants, R-455A (R-744/32/1234yf) and R-463A (R-744/32/125/1234yf/134a), to improve the thermodynamic performance of pure CO2 refrigerants. The thermodynamic energy and exergy analysis and system optimization of an AAC system for the new zeotropic refrigerant blends compared to carbon dioxide (R-744), using Aspen HYSYS software, were investigated. The influence of cooler/condenser pressure, average evaporator temperature, cooler/condenser outlet temperature, and refrigerant flow rate on the cycles’ COP and exergy efficiency were conducted and are presented. The results showed that, at the same operating condition parameters, the cycle COP improved by 57.6 and 76.5% when using R455A and R463A instated of R744, respectively, with the advantage of reducing leakage problems due to the higher operating pressure of R744 (5–7 times higher than those of R455A and R463A), as well as requiring heavy equipment, but at optimal operating condition parameters, R744 and R-463A had a maximum COP of 14.58 and 14.19, respectively. The maximum COPs of R744, R455A, and R463A based on the optimal pressure of the cooler/condenser were 3.1, 4.25, and 5.4, respectively. Additionally, regarding the need for environmentally friendly air conditioning systems with acceptable performance in cars due to their impact on the environment and their contribution to global warming, the blend R455A is recommended for use as a refrigerant in AAC systems.