Background: Atherosclerosis is a kind of chronic cardiovascular disease, and Tanshinone IIA (Tan) is a naturally derived anti-inflammatory compound. In this study, we aim to explore the biological role of Tan and regulatory mechanism in atherosclerosis.Methods: Firstly, the model of atherosclerosis mice was constructed. The area of atherosclerosis, the level of blood lipid and the content of inflammatory factors were measured in mice treated with Tan. After that, the differentially expressed microRNAs (miRNAs) were obtained by microarray analysis of mice plasma. The effect of miR-23b on cell migration ability, adhesion ability and inflammatory factor level of macrophages treated with Tan. After that, we determined the target mRNA of miR-23b through the bioinformatics analysis and the dual luciferase reporter gene assay. THP-1 macrophages were treated with miR-23b mimic or si-TRIB1 to detect the activity of the TLR4/NF-κB signaling pathway via immunohistochemistry.Results: Tan injection significantly improved atherosclerosis inflammation in mice, especially in mice treated with 90 mg/kg dose. miR-23b was obtained by differential screening, which can significantly inhibit the drug effect of Tan, and aggravate the occurrence of atherosclerosis. miR-23b targeted TRIB1, the decrease of TRIB1 also inhibited the drug effect of Tan. The up regulation of miR-23b enhanced the activity of TLR4/NF-κB pathway, and TLR4/NF-κB pathway inhibited the drug effect of Tan on the inflammatory response.Conclusion: Overall, Tan could protect macrophage against inflammation via inactivating TLR4/NF-κB pathway by down-regulating miR-23b and upregulating TRIB1, providing a novel theoretical foundation for treatment of atherosclerosis.