Major depression (MD) is a major public health problem which has a substantial impact on individuals and society. Although it is usually treated with antidepressant in primary care, these therapies accompanied with serious side effects. In the clinic of Chinese medicine, Xiao-Yao-San is the first option for MD with little side effects. Although with clear therapeutic effects, its therapeutic mechanism is obscure. In this study, by integrating leading biomedical knowledge databases, though bioinformatics analysis, we explored the potential therapeutic mechanism of Xiao-Yao-San for MD. The therapeutic mechanism analysis covers aspects of Chinese herbal medicine, chemical compound, target protein, OMIM genes, and pathways enriched. As a result, Xiao-Yao-San's 4 target proteins e.g., ADRB2R, B2AR, ADRB2, and MC4R can be matched in MD's OMIM genes which are mainly enriched in pathways of signal transduction. This research demonstrates that Xiao-Yao-San's target proteins may regulate a wide range of different pathways associated with MD.