Background and Purpose Inflammation and lipid accumulation are key events in atherosclerosis progression. Arsenic trioxide (ATO) has been reported to prevent vascular restenosis by promoting smooth muscle apoptosis and rapid initialization. However, its specific role and mechanism underlying its role in atherosclerosis remain unknown. Herein, we evaluated whether ATO suppresses atherosclerotic plaque development and instability. Experimental Approach ApoE-/- mice were fed a high-fat diet for 3 months and treated with ATO every alternate day for 30 days. The carotid artery and serum samples were collected to determine atherosclerotic lesion size, histological features, and related protein and lipid profiles. In vitro, RAW264.7 or THP-1 cells were stimulated using oxidized low-density lipoprotein (ox-LDL) or LPS to explore the anti-inflammatory and anti-pyroptosis effects of ATO. Key Results ATO reduced atherosclerotic lesion formation and plasma lipid levels in ApoE-/- mice. Additionally, it reduced the levels of various pro-inflammatory factors, including IL-6 and TNFα, in the serum and aortic plaques, but increased the IL-10 level. Mechanistically, ATO promotes the CD36-mediated internalization of ox-LDL, which may explain the reduction in blood lipid levels. Further, ATO reduced TLR4 expression in plaques and macrophages and inhibited LPS-induced p65 nuclear translocation and IκB-α degradation. Conclusion and Implications ATO has the potential atheroprotective effects, especially in macrophages. The mechanisms include inhibition of CD36-mediated foam cell formation, inflammatory responses, and pyroptosis via the suppression of TLR4/NF-κB and NLRP3 activation. Our findings provide evidence for the potential atheroprotective value of ATO.