Background. Although the traditional Chinese medicine Shan-Zhu-Yu may be efficacious against depression, its mechanism of action is unknown. In this study, we aimed to explore the possible mechanisms of action of Shan-Zhu-Yu in the treatment of depression using network pharmacology. Methods. The active ingredients and targets of Shan-Zhu-Yu were obtained from the Traditional Chinese Medicine System Pharmacology Database (TCMSP) database and converted into gene names using UniProt. Then, the target genes of depression were collected using GeneCards and OMIM. Drug disease intersection genes were obtained using a Venn tool, and a protein-protein interaction network was constructed using STRING. Cytoscape was used to construct an active ingredients-targets-drug-disease network. GO and KEGG pathway enrichment analyses were performed using DAVID. Furthermore, Autodock was used to evaluate drug and target binding and explore possible molecular mechanisms. Results. We identified 9721 disease genes, 13 active ingredients, 50 target genes, and 48 drug disease intersecting genes. The results of the GO enrichment analysis suggested that Shan-Zhu-Yu affects the activity of G protein-coupled amine, neurotransmitter, steroid hormone, nuclear, and G protein-coupled neurotransmitter receptors in the treatment of depression by acting on hormone and nuclear receptor binding. The main signaling pathways were associated with neuroactive ligand-receptor interaction, calcium, cGMP-PKG, apoptosis, estrogen, p53, and AGE-RAGE. Molecular docking confirmed that the active components of Shan-Zhu-Yu (e.g., telocinobufagin and beta-sitosterol) docked suitably with NR3C1, Bax, Bcl-2, and caspase-3. Shan-Zhu-Yu may exert its therapeutic effects on depression via multiple targets and pathways. Conclusions. The present study elucidates that Shan-Zhu-Yu suppresses the expression of Bax and caspase-3 and promotes that of NR3C1 and Bcl-2 through neuroactive ligand-receptor interaction and apoptosis signaling pathways. Therefore, Shan-Zhu-Yu is a potential treatment option for depression, and the results of this study will provide new reference points for future experimental research and a scientific basis for its widespread clinical application.