Background:S. aureus (Staphylococcus aureus) infection imposes a serious burden to global healthcare systems. WWXDY (Wuweixiaoduyin) is a traditional Chinese medicine, and it is usually used to treat infections in China. This study aimed to explore the active compounds, therapeutic targets, key pathways, and potential mechanisms of WWXDY in the treatment of S. aureus infection. Materials & Methods:Data related to active compounds and therapeutic targets of WWXDY for treating S. aureus were collected from DisGeNET, GeneCards, and DrugBank databases. To explore the roles of the active targets in gene function and signaling pathways, KEGG (Kyoto Gene and Genomics Encyclopedia) pathway enrichment and GO (Gene Ontology) analyses of the 122 target genes in the PPI (protein-protein interaction) network were performed. We further performed NP (network pharmacology) by using a network analyzer to screen 30 key targets. Results:A total 92 active compounds of WWXDY were screened. The 122 overlapped genes were found from 785 therapeutic targets and 684 S. aureus-related genes. Besides, 92 active compounds of WWXDY, such as mandenol, ethyllinolenate, eriodyctiol, secologanic dibutylacetal_qt, etc., were identified. The PPI network of the effective ingredients of WWXDY in treating S. aureus infection identified the top 30 genes, including IL-6 (interleukin-6), TNF-α (tumor necrosis factor-α), VEGFA (vascular endothelial growth factor A), AKT1, CXCL8, MAPK3 (mitogen-activated protein kinase 3), TLR (toll-like receptor 4), IL-1β, EGFR (epidermal growth factor receptor), and MMP9 (matrix metalloproteinase-9). Conclusion:The GO functional and KEGG pathway enrichment analyses indicated that 122 overlapped genes were mainly enriched in COVID-19, AGE-RAGE signaling pathway, C-type lectin receptor signaling pathway, Pertussis, and Chagas disease. Our findings indicated the active compounds and therapeutic targets of WWXDY in treating S. aureus infection, as well as its potential mechanisms.