Objective To investigate the optimal extraction process for Siwei Huanglian Lotion by the orthogonal design. Methods Alcohol extraction was performed for Siwei Huanglian Lotion and the L9 (34) orthogonal design was used to determine times of extraction, alcohol concentration, extraction time, and alcohol amount. With the content of baicalin, berberine hydrochloride, and emodin and the yield of dry extract as indices, the comprehensive scoring method was used to analyze data and determine the optimized extraction process. Results The optimal alcohol extraction process for Siwei Huanglian Lotion was to mix 80% alcohol with the medicinal material (prescribed dose) at a ratio of 12∶1 and to extract 3 times (1.5 hours each time). Conclusion This optimal extraction process for Siwei Huanglian Lotion is stable and feasible and can be used for the production of Siwei Huanglian Lotion.