Abstract: Objective: To establish the optimal preparation process of Zhongjiexiao granules and develop its quality control method. Methods: The drug-excipient ratio, ethanol volume fraction, and ethanol mass fraction were selected as investigation factors, with the forming rate, hygroscopicity, and flowability (angle of repose) as evaluation indicators. The entropy weight method was used to calculate comprehensive scores, and combined with Box-Behnken response surface methodology to determine the optimal forming process. Thin-layer chromatography (TLC) was employed for qualitative identification of Sarcandrae Herba, Paeoniae Radix Alba, Millettiae Speciosae Radix, Prunellae Spica, Hedyotis diffusae Herba, and Bupleuri Radix. High-performance liquid chromatography (HPLC) was applied to determine the contents of isofraxidin and paeoniflorin. Results: The optimal forming process parameters were screened out as follows: drug-excipient ratio of 1:1, ethanol volume fraction of 77%, and ethanol mass fraction of 35%. Under these conditions, the average comprehensive score reached 86.82. The TLC identification showed clear and well-separated spots with no interference from negative controls. The HPLC results indicated that the contents of isofraxidin and paeoniflorin were not less than 508.54 μg/g and 1.41 mg/g, respectively. Conclusion: The forming process optimized by Box-Behnken response surface methodology is stable and feasible. The established TLC and HPLC methods are specific and reproducible, providing reliable support for the scale-up production and quality standardization of Zhongjiexiao granules.