Aim To investigate the pharmacology mechanism of Sanhuang Xiexin decoction in the treatment of atherosclerosis. Methods All the chemical components and the targets related to Sanhuang Xiexin decoction were searched by the traditional Chinese medicine system pharmacology platform (TCMSP), the oral bioavailability (OB) ≥30% and drug likeness(DL) ≥ 0.18 were used as the screening conditions for molecular compounds and the comparative Toxicogenomics Database (CTD) were used to screen the genes related to atherosclerosis. The network map was constructed by Cytoscape 3.6.1 soft ware and the DAVID database was used for pathway annotation and analysis. ResultsThe compounds-targets-pathway network of Sanhuang Xiexin decoction related to atherosclerosis contained 41 compounds, 22 corresponding targets and 39 signaling pathway. The top four compounds were quercetin, baicalein, wogonin and emodin. The top five targets were prostaglandin G/H synthase 2 (PTGS2), intercellular adhesion molecule 1 (ICAM-1), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor (TNF) and interleukin-6(IL-6). Related pathway were HIF-1 signaling pathway, cytokine-cytokine receptor interaction, NF-κB signaling pathway, VEGF signaling pathway, arachidonic acid metabolism and PPAR signaling pathway. Conclusion The active components of Sanhuang Xiexin decoction may regulate arachidonic acid metabolism, NF-κB signaling pathway, VEGF signaling pathway in the treatment of atherosclerosis mainly through PTGS2, ICAM-1, MMP-9, IL-6 and other targets.