As an efficient and environment-friendly solution to replace traditional fuel-fired boiler, CO2 air source heat pump water heater (HPWH) is widely used in the commercial and residential water heating. In order to achieve the optimal performance of CO2 air source HPWH systems, the effects of electronic expansion valve (EEV) opening and inlet water flow rate on system performance are experimentally studied and the optimal matching of the two parameters are obtained in this study. Then, the relationship between the optimal high pressure and the optimal matching of EEV opening and water flow rate is discussed. Finally, a new parameter, the endpoint temperature difference (ΔTep), is defined and a novel control strategy of ΔTep = 0 is proposed to determine the optimal high pressure. The results indicate that the optimal matching of EEV opening and water flow rate corresponds to the optimal high pressure and the best COPheat of system. A smaller ΔTep corresponding to a better matching degree and a larger system COPheat. The maximum deviation between the high pressure determined by the proposed new control strategy and the optimal high pressure is less than 1.8 %, and the system COPheat under the proposed new control strategy can achieve more than 97.6 % of the maximum COPheat. Therefore, the proposed control strategy in the paper is better than that of the commonly used off-line optimal high pressure correlation and can provide guidance for the efficient operation of the CO2 air source HPWH system.