Objective:This study was to use network pharmacology techniques to predict the key targets of Compound prescription of sour jujube kernel (ZSSF) for depression, and to verify its mechanism of action using a zebrafish model of rifampicin-induced depression. The drug targets of ZSSF were retrieved from the TCMSP database, and the target names were corrected using the UniProt database. Targets related to depression were identified using the GeneCards, OMIM, and NCBI databases. Protein-protein interaction information for the shared targets was predicted using the String database. The collected data was then analyzed using the Metascape database to determine the enrichment of GO and KEGG pathways. The results were visualized using microbiotics. Behavioral experiments and RT-qPCR experiments were conducted to verify the therapeutic effect of ZSSF on depression using a zebrafish depression model induced by Risperdal.Results: A total of 188 targets were screened to find the intersection of depression and ZSSF. The protein-protein interaction results showed that ZSSF primarily targeted TNF-α, IL-2, IL-6, IL-1β, and IL-10 for its antidepressant effect. KEGG pathway enrichment analysis revealed that ZSSF exerted its therapeutic effect on depression through various signalling pathways such as the TNF signalling pathway, PI3K-Akt signalling pathway, and cGMP-PKG signalling pathway. The results of the animal experiments showed that the treatment groups with high, medium, and low doses of ZSSF exhibited significant improvements in distance of movement under acoustic and light stimulation compared to the model group. The speed of movement was also significantly faster. Additionally, the mRNA expression levels of TNF-α, IL-2, IL-6, IL-1β, and IL-10 were up-regulated in the brain tissues of zebrafish in the high, medium, and low dosage groups of ZSSF compared to the model group.Conclusion: ZSSF exerts its antidepressant effect through multiple components and targets. Its antidepressant effect may be associated with the inhibition of inflammatory factors.