Objective To investigate the optimal water extraction process for Painong Powder. Methods With the content of three components (naringin, neohesperidin, and paeoniflorin) in water extract and extract yield as the indices of evaluation, Box-Behnken response surface methodology was used to evaluate the effect of solid-liquid ratio, soak time, and extraction time on extraction process. Results The optimal process conditions for water extraction of Painong Powder were 15 times of water, a soak time of 67 minutes, and an extraction time of 74 minutes. Conclusion The water extraction process for Painong Powder optimized by Box-Behnken experimental design is feasible and has good predictability.