Kaixinsan powder (KXS), a classic prescription of traditional Chinese Medicine (TCM), is widely used in the treatment of depression, but its mechanism remains unclear. The network pharmacology method was used to constructe the "herb-component-target" network, and elucidated KXS potential mechanisms of action in the treatment of depression. Moreover, molecular docking was applied to valid the important interactions between the ingredients and the target protein. The "herb-component-target" network indicated that the ingredients of Girinimbin, Gomisin B and Asarone, and the protein targets of ESR, AR and NR3C1 mostly contribute to the antidepressant effect of KXS. KEGG pathway analysis highlighted the most significant pathways associated with depression treatment, including neuroactive ligand-receptor interaction pathway, serotonergic synapse pathway, PI3K-Akt signaling pathway and MAPK signaling pathway. Go enrichment analysis indicated that the mechanism of KXS in treating depression was involved in the biological process of GPCR signal transduction, hormone metabolism and nerve cell apoptosis. Moreover, molecular docking results showed that Polygalaxanthone III, Girinimbine and Pachymic acid performed greater binding ability with key antidepressant target 5-HTR. In conclusion, this study preliminarily revealed key active components in KXS, including Gomisin B, Asarone, Ginsenoside Rg1, Polygalaxanthone III and Pachymic acid, could interact with multiple targets (5-HTR, DR, ADRA, AR, ESR, NR3C1) and modulate the activation of multiple pathways (Neuroactive ligand -receptor interaction pathway, serotonergic synapse pathway, PI3K-Akt signaling pathway and MAPK signaling pathway).