To reduce the operating pressure and broaden the range of condensation temperature, it is proposed to mix CO2 with organic fluid to form a zeotropic mixture. However, how CO2-based mixtures perform in the combined power and cooling system is still an open question. Therefore, in this study, aiming at the newly proposed system for waste heat recovery, CO2/R600a and CO2/R601a mixtures are first employed to produce power and cooling. Based on the established models, the energy and exergy performances of combined system with CO2-based mixtures are analyzed. The effects of key parameters on system performances are investigated. On this basis, the performance optimization is conducted to maximize net work by using a genetic algorithm (GA), and the optimal system performance of mixtures and pure CO2 are compared. The results indicate that under the basic operating conditions, the net works of CO2/R600a (0.5/0.5) and CO2/R601a (0.5/0.5) are 2717.93 kW and 1145.98 kW, respectively. The optimal results indicate that among the considered working fluids, the highest specific net work is always obtained by CO2/R600a system. This study will be helpful to the development of combined power and cooling systems with CO2-based mixtures.