Abstract: Objective: Revealing the anti-depression mechanism of Akebiae Fructus by network pharmacology technology. Methods: The active compounds and its corresponding depression-related targets of Akebiae Fructus were mined from the TCMSP, PharmMapper, Swiss TargetPrediction, and GeneCards databases. The protein-protein interactions were gained from the String database. The compound-target and PPI networks were built by Cytoscape software. The DAVID database was exploited for enrichment analysis of GO and KEGG signaling pathways for key targets. Finally, molecular docking was carried out for verification using AutoDockTools-1.5.6 software. Results: The 6 active compounds of Akebiae Fructus were identified, including calceolarioside B, stigmasterol glucoside, and oleanolic acid, etc. 8 major depression-related targets were predicted, such as EGFR, MAPK1/8, SRC, HSP90AA1, AR, etc. 16 depression-related signaling pathways were modulated, namely the prolactin signaling pathway, ErbB signaling pathway, GnRH signaling pathway, focal adhesion, etc. The results of molecular docking showed that the kernel components had good binding activity with the key targets. Conclusion: Akebiae Fructus exerted anti-depression effect through the comprehensive combination of multiple components, multiple targets and multiple pathways.