In order to optimize the cascade refrigeration system, the thermodynamic models of cascade refrigeration systems were established in this study, and the effects of low and high temperature stage condensation temperature, and regenerator position on the performance of R449A/CO₂, NH₃/CO₂, R404A/CO₂ cascade refrigeration systems were compared and analyzed. The results show that: at the same low temperature stage evaporation temperature, the optimal low temperature stage condensation temperature of the NH₃/CO₂ system is lower than that of the R449A/CO₂ and R404A/CO₂ systems, and the best COP of the NH₃/CO₂ system differs from R449A/CO₂ by about 2%, which is much higher than that of the R404A/CO₂ system. Adding the regenerator to the CO₂ low temperature stage of the cascade system will reduce performance of system. However, Adding the regenerator to the high temperature stage will reduce the performance of the R449A/CO₂ and NH₃/CO₂ systems and increase the performance of the R404A/CO₂ system. R449A has excellent performance in cascade refrigeration system and can be used widely as low GWP refrigerant.