This study investigated the anti-acne mechanism of Salviae Miltiorrhizae Radix et Rhizoma (SMR) and Epimedii Folium (EF) using network pharmacology and experimental validation.The datasets of acne-related differentially expressed genes were downloaded from the GEO database and combined compound-target relationships from TCMSP,TM-CM,ETCM,and SwissTargetPrediction.The analysis showed that 42 active compounds and 16 candidate targets were fished out.GO,KEGG enrichment analysis,and protein-protein interaction network construction was performed to screen potential targets and hub targets.Molecular docking analysis results indicated that core compounds bound strongly to the targets.Finally,the anti-acne activity of SMR-EF was confirmed through bacterial inhibition,LPS-stimulated RAW 264.7 macrophages and Cutibacterium acnes-induced HaCaT keratinocytes.The main bioactive components of SMR-EF,salvianolic acid A,salvianolic acid G,isotanshinone IIB,epimedoside and icariside II were screened to bind the target proteins,including prostaglandin G/H synthase 2 (PTGS2),matrix metalloproteinase 3 (MMP3),MMP9,plasminogen activator urokinase (PLAU),and C-C motif chemokine receptor 1 (CCR1), which could potentially regulate interleukin-17 (IL-17) signaling pathway.The growth and biofilm formation of C. acnes were inhibited by SMR-EF (1∶1) in vitro, and SMR-EF distinctly decreased the secretion of TNF-α,IL-6,and NO secretion in LPS-stimulated RAW 264.7 macrophages, and mediated downregulation of Toll-like receptor 2 (TLR2),TLR4,and IL-8 in C. acnes-induced HaCaT keratinocytes. RT-qPCR also confirmed that SMR-EF downregulated the expression of PTGS2, MMP3, MMP9, PLAU, and CCR1.Collectively,SMR-EF effectively inhibits C. acnes and alleviates acne-associated inflammation,potentially through IL-17 pathway modulation.