Atherosclerosis is thickening of arterial wall, which causes several complications. This study evaluated the protective effect of verbascoside against atherosclerosis and the potential molecular mechanism involved. Atherosclerosis was induced by administering a high-fat diet to rats for 3 months and vitamin D3 for 4 days. Verbascoside (2 mg/kg p.o.) was administered for 6 weeks after the end of high-fat diet administration. The serum levels of inflammatory mediators and the lipid profile were determined, and atherosclerotic lesions were observed via Sudan IV staining. Moreover, immunohistochemical analysis, Western blot assay and qRT-PCR were performed to determine the effect of verbascoside on the AMPK/mTOR pathway in atherosclerosis. The results reveal that verbascoside ameliorated the altered serum levels of inflammatory mediators and the lipid profile as well as the organ coefficients in the atherosclerotic rats. A significant decrease in atherosclerotic lesions was detected in the verbascoside-treated group than the atherosclerosis group. AMPK and mTOR mRNA expression decreased in aortic tissues of the verbascoside-treated group compared to the atherosclerosis group. These data suggest that verbascoside ameliorates atherosclerosis by decreasing hyperlipidaemia in atherosclerosis induced by a high-fat diet.