OBJECTIVES: Atherosclerosis significantly contributes to global cardiovascular mortality. Macrophage polarization and foam cell formation via oxidized low-density lipoprotein uptake are key drivers of plaque progression and instability. Targeting these processes may offer a promising therapeutic approach. This study aimed to investigate the potential therapeutic effects of Shanhuang Jiangzhi tablets (SHJZT) using apolipoprotein E-deficient mice and RAW264.7 macrophage-based experimental models. METHODS: Key assays, including oxidized low-density lipoprotein-induced foam cell formation and lipopolysaccharide (LPS)-induced macrophage polarization, were performed to elucidate the regulatory effects of SHJZT, with a particular focus on the reactive oxygen species (ROS)/Toll-like receptor 4 (TLR4)/NF-κB signaling pathway. KEY FINDINGS: In vivo, SHJZT treatment significantly attenuated atherosclerotic lesion development, improved lipid metabolism, and enhanced reverse cholesterol transport by regulating ABCA1 and ABCG1 expression, thereby suppressing foam cell formation. Furthermore, SHJZT promoted macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Mechanistic investigations revealed that SHJZT mitigated LPS-induced ROS production and inhibited the activation of the TLR4/NF-κB signaling cascade in vitro. Specifically, SHJZT downregulated key pathway components, including TLR4, MYD88, and phosphorylated NF-κB p65, in high-fat diet-induced atherosclerosis. CONCLUSION: SHJZT exerts anti-atherosclerotic effects by modulating macrophage polarization and inhibiting foam cell formation through the suppression of ROS/TLR4/NF-κB signaling pathway.