Vitamin C (VC) liposomes were prepared by the rapid expansion of supercritical solution process (RESS) in this study. The combined effects of temperature, pressure, and feeding ratio of VC against phosphatidylcholine (PC) on the drug loading content of the prepared liposomes were determined and discussed using response surface analysis. The results revealed that these conditions showed a very complicated influence, but the experimental data could be well predicted by the model obtained in this study. Under the optimal operating conditions (the pressure of 25 MPa, the temperature of 48 °C, and the feed ratio of VC against PC of 0.25) calculated by the present model, the VC loaded liposomes were successfully prepared with the loading content of 75.38 ± 1.03%. The particle size, PDI and Zeta-potential of the prepared samples was 270.4 ± 5.2 nm, 0.254 ± 0.010 and −41.7 ± 0.9 mv, respectively. The experimental loading content value was in accordance with the predicted one, indicating that the present model could be used to predict the loading content of the prepared VC liposomes using RESS.