Aim To explore the effect of TanshinoneⅡA(TanⅡA) on macrophage polarization by inhibiting histone deacetylase 3(HDAC3). Methods Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) was applied to screen drug targets of TanⅡA and therapeutic targets of atherosclerosis(As). The intersection genes were enriched and visualized by KEGG pathway analysis and Cytoscape 3.7.1 software, respectively. THP-1 monocytes were induced as adherent macrophages by phorbol 12-myristate- 13-acetate(PMA), and divided into four groups:M0 group, oxidized low density lipoprotein(ox-LDL) group, TanⅡA＋ox-LDL group and ox-LDL＋HDAC3 siRNA group. Flow cytometry, immunofluorescence and qRT-PCR were used to detect the change of polarization and expression of HDAC3 mRNA in macrophage. Results Twenty-three intersection genes were obtained of TanⅡA drug targets and As therapeutic targets by Bioinformatics analysis. The top twenty signal pathways were selected for visual analysis and displayed that these genes concentrated in signaling pathways such as atherosclerosis, fluid shear force and TNF signaling pathway, among which JUN, FOS, RELA and NFKBIA, were involved in the regulation of macrophage polarization. Results of Flow cytometry, immuno fluorescence and qRT-PCR showed that ox-LDL could significantly increased the expression of CCR7 and CCL2 in M0 macrophages. Compared with ox-LDL group, HDAC3, CCR7 and CCL2 expression decreased in TanⅡA＋ox-LDL group, consistent with ox-LDL＋HDAC3 siRNA group. Conclusion TanⅡA could effectively prevent ox-LDL-induced macrophage polarization toward M1 direction, the mechanism may be mediated by regulating HDAC3 expression.