Objective To optimize the flash extraction process of Huangyu Shenshu Granules based on Box-Behnken design-response surface methodology. Methods The extraction yields of morroniside and loganin, as well as the yield of dry extract, were used as evaluation indices. The rotation speed, liquid-solid ratio, and extraction time were selected as the investigation factors. Based on preliminary experiments, combined with Box-Behnken design-response surface methodology, the flash extraction process of Huangyu Shenshu Granules was studied and optimized. Results The optimal condition for the flash extraction of Huangyu Shenshu Granules were taking water as the extraction solvent, with a rotation speed of 4, 560 r/min, a liquid-solid ratio of 23 mL/g, and an extraction time of 85 s. Conclusion The flash extraction process established based on Box-Behnken design-response surface methodology is rapid and efficient, and suitable for the subsequent industrialization development of Huangyu Shenshu Granules.