OBJECTIVE: To investigate the mechanism underpinning the effect of Chaihu Shugan San(柴胡疏肝散, CHSGS) on major depressive disorder(MDD).METHODS: We searched the compound components of from seven herbal ingredients of CHSGS from TCMSP, Sym Map, ETCM, NPASS databases, and the chemical structure of the compound from PubChem, and collected the compound targets from TCMSP and Target Net databases, and MDD-related targets from Disease Gene Network. We established protein-protein interaction in the STRING database.Through gene mapping, topology analysis and enrichment analysis, the core targets and pathways of CHSGS for MDD, and the involved biological processes(BP), cell components(CC), and molecular functions(MF) were predicted.RESULTS: We collected a total of 1135 CHSGS compounds. After screening by ADME standards and the five rules of Ribinski, we obtained 99 different chemical components with different chemical structures, and related targets of 183 different CHSGS compounds. In the Disease Gene Network, a total of 740 relevant targets for MDD were collected. Through gene mapping and topological analysis, 62 related targets of CHSGS for MDD, 24 targets with topological Chinese herbal medicine were obtained. Through enrichment analysis, 10 relevant pathways and 3 core pathways were obtained with the involvement of 127 BP, 27 CC, and 43 MF.CONCLUSION: There are multiple targets and signaling pathways are involved in the action of CHSGS in the treatment of MDD.