To improve the extraction yield of effective components from Xiao ’er Qushi Zhiyang Granules and enhance the stability of preparation quality, this study optimizes the water extraction process of Xiao ’er Qushi Zhiyang Granules by combining single-factor experiments with the Box-Behnken response surface methodology. The amount of added water, extraction time and soaking time were selected as investigation factors, while the contents of rosmarinic acid, paeoniflorin and obacunone and the yield of dry extract were adopted as evaluation indicators. A combined weighting method of Analytic Hierarchy Process-Entropy Weight Method (AHP-EWM) was applied to calculate the comprehensive score. Response surface methodology was employed to analyze the interaction between factors, optimize process parameters, and carry out methodological research and process validation. The results show that the optimal water extraction process is as follows: adding eight times the amount of water, soaking for 30 minutes, extracting two times, with a total extraction time of three hours. Under this process, the comprehensive score is 95.80 with RSD = 0.96%, and the relative error compared with the predicted value is less than 10%. In conclusion, this process is stable, feasible and has good reproducibility, which can sufficiently extract paeoniflorin, rosmarinic acid, obacunone and other core pharmacodynamically active components in the formula, and can provide a reference for the industrial production and quality control of Xiao ’er Qushi Zhiyang Granules.