Using pomegranate and medlar as the main raw material, the fermentation conditions were optimized by response surface method based on single factor test. Pomegranate wolfberry juice ratio, yeast inoculation quantity, and fermentation temperature were chosen as the independent variables. The alcohol content of pomegranate-medlar wine was chosen as the response value. The Box-Behnken central composite experimental design mathematical model was used to carried out response surface analysis. The results showed that the surface fitting of the regression equation was good. Under the optimal fermentation conditions with fermentation temperature of 28 ℃，ratio of pomegranate to wolfberry of 2∶1, and yeast inoculum of 3% conditions, the alcohol content reached 9.94%vol, which was consistent with the predicted model value of 9.93%vol. This wine had pure and thick fragrance, pleasant taste, shiny red brown color, and high transparency. Optimization of the fermentation process of pomegranate and wolfberry wine by response surface methodology is significant.