Cryogen spray cooling (CSC) was proved to be an effective method to avoid the hyper-thermal injury in epidermal layer during the laser treatment of port wine stain (PWS). A numerical analysis was performed to show the thermal history during the CSC process. The analysis reveals that CSC does not only reduce the surface temperature and protect the skin surface from burning but also makes a high energy density possible to improve the clinic outcomes. The impact of the heat transfer coefficient and the initial tissue temperature on the cooling effect of CSC was also examined. We find that the surface temperature decreases as the heat transfer coefficient increases and a high initial temperature improves the clinical outcomes by increasing the final temperature in the PWS layer. However, a high initial temperature might increase the possibility of heat injuries, which should be avoided by extending the cryogen spraying time.