Objective: To screen the optimal water extraction process for Alisma orientale formula granules. Methods: A three-variable single-factor method was adopted, with extraction time, water addition volume, and extraction frequency as horizontal factors, and acetyl alisma C content and alisma extract rate as evaluation indicators. The Box-Behnken response surface method was used to screen the water extraction process of Alisma formula granules, and the best water extraction process method was selected. Results: The water extraction process of the optimized Alisma orientale formula granules is to add 10 times the amount of water, boil for 1.5 hours, and extract three times. Conclusion: The preferred extraction process is stable and feasible, providing a basis for the large-scale industrial production of Alisma orientale formula granules.