Aim To investigate the antagonistic effect and mechanism of amarogentin (MAG) on atherosclerosis induced by high fat diet (HFD) in mice. Methods Thirty ApoE－/－mice were randomly divided into control group (normal diet), HFD group and HFD+MAG group, with 10 mice in each group. HFD+MAG group was given 50 mg/kg MAG daily for 12 weeks. Blood lipid level was measured by biochemical detector. The deposition of plaque in aorta was observed by oil red O staining. The pathological morphology of aorta was observed by hematoxylin-eosin (HE) staining.Mac-3 immunohistochemistry was used to observe the aggregation of macrophages in aorta. The expression and distribution of NOD-like receptor pyrin domain containing 3 (NLRP3) were observed by immunofluorescence location staining. The expression levels of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and Caspase-1 subunit p20 in aorta were detected by Western blot. Results The levels of triglyceride, total cholesterol and low-density lipoprotein cholesterol in HFD+MAG group were respectively decreased to 88.39%, 74.85% and 64.97% of HFD group (P＜0.05), and the level of high-density lipoprotein cholesterol was increased to 142.18% of HFD group (P＜0.05), the plaque area was reduced to 45.16% of HFD group (P＜0.05), the pathological morphology of aorta was improved, macrophage deposition and the proportion of NLRP3 positive macrophages in plaque was reduced, and the expression levels of NLRP3, ASC and Caspase-1 subunit p20 in aorta were respectively decreased to 45.58%, 53.28% and 42.35% of HFD group (P＜0.05). Conclusion MAG has significant antagonistic effects on atherosclerosis mice induced by high fat diet, which may be related to the inhibition of NLRP3 inflammasome activation of macrophages in plaques.