Scope Atherosclerosis is the underlying pathogenesis of cardiovascular events caused by inflammation, and dietary intervention has been recommended as one fundamental prevention strategy. Herein, the anti-arteriosclerotic properties of quercetin are investigated by modulating galectin-3 (Gal-3)-NLR family, pyrin domain-containing 3 (NLRP3) pathway. Methods and results Plaques from ApoE(-/-) mice fed by high-fat diet (HFD) with or without quercetin (100 mg (kg center dot bw)(-1)) for 16 weeks, and carotid plaques from patients with carotid stenosis are collected for histopathological examinations and molecular mechanism assays. Quercetin significantly alleviates atherosclerotic lesions and reduces lipid retention caused by HFD. Proteomic technology identified Gal--3 increased by HFD but lowered by quercetin. Furthermore, immunofluorescence and immunohistochemistry exhibit higher expressions of Gal-3 and NLRP3 in carotid plaques and plaques from HFD-fed mice, which are concurrently down-regulated by quercetin. Similar to TD139, quercetin dramatically suppresses NLRP3 inflammasome activation in oxidized low-density lipoprotein-laden macrophages, and accordingly alleviates cellular steatosis and IL-1 beta secretion, which is abolished by recombinant Gal-3. Co-immunoprecipitation shows Gal-3 binding to NLRP3 promotes inflammasome activation. Conclusion Gal-3 initiates inflammatory lesions by activating NLRP3 inflammasome which functions as a candidate target of quercetin exerting favorable anti-atherogenic effects. The findings highlight a promising strategy for atherosclerosis prevention and treatment by naturally-occurring quercetin.