Objective To investigate the therapeutic effects of amygdalin（AMY）on atherosclerosis and to elucidate its possible mechanisms. Methods Treatment with different doses of AMY intervention on human coronary artery endothelial cells（HCAECs），HCAECs were divided into four groups：control，ox⁃LDL，AMY low dose group（50 μg/mL），and AMY high dose group（100 μg/mL）. Pyroptosis proteins（caspase⁃1 and GSDMD） as well as histone demethylase（JMJD3）and galectin ⁃3（Gal ⁃3）expression levels were determined by Western blotting. IL ⁃ 1β and IL ⁃ 18 mRNA expression by RT ⁃ qPCR. TUNEL assay was used to detect the death rate of HCAECs. ChIP assay was used to detect the enrichment of JMJD3 and H3K27me3 on Gal⁃3 promoter region. The ef⁃ fect of Gal⁃3 on Amy inhibition of ox LDL induced pyroptosis in HCAECs was further analyzed after overexpression of Gal⁃3. 40 apolipo protein E⁃deficient（ApoE）-/- male mice were divided into control group，model group，2.5 and 5 mg/kg AMY group. Oil red O staining was used to observe lipid deposition and plaque formation in mice aortas. Serum levels of total cholesterol（TC），triglycerides（TG），high⁃density lipoprotein cholesterol（HDL⁃C），and low⁃density lipoprotein cholesterol（LDL⁃C）were measured by enzymatic colorimetric methods. Results Versus the control group，AMY had no significant effect on cell viability，50 and 100 μg/mL AMY intervened cells showed no significant difference in cell viability compared to the control at 24 h，and a significant decrease in cell viability compared to the control at 36 h and 48 h. Compared to ox⁃LDL，the protein levels of Caspase⁃1，GSDMD， Gal⁃3 and JMJD3，the mRNA expression of IL⁃1β and IL⁃18，and the rate of TUNEL positive cells decreased in a dose ⁃ dependent manner 50 and 100 μg/mL AMY. The enrichment of JMJD3 on Gal ⁃ 3 promoter region was de⁃ creased and H3K27me3 was increased in HCAECs after AMY intervention. The expression levels of Gal⁃3，caspase⁃1， GSDMD，IL⁃1β，and IL⁃18 and the percentage of TUNEL positive cells within HCAECs were increased in the ox⁃LDL+AMY+pcDNA⁃Gal⁃3 group compared with the ox⁃LDL+AMY+pcDNA⁃3.1 group. Compared with the model group，the lipid deposition in the aorta was reduced and the percentage of atherosclerotic lesion area was decreased in 2.5 or 5 mg/kg AMY mice. The concentrations of TG，TC，LDL and the expression levels of Gal⁃3，caspase⁃1， GSDMD，IL⁃1β，and IL⁃18 were decreased in a dose⁃dependent manner，while the content of HDL was increased. Conclusion AMY may contribute to the amelioration of atherosclerosis induced pyroptosis by participating in the regulation of JMJD3 mediated Gal⁃3 demethylation.