Verbascoside, abundant in olive mill wastewater, is a phenylethanolic glycoside with a wide range of pharmacological activities. Atherosclerosis (AS) is a common metabolic disease and abnormal lipid metabolism in liver is inseparable from its formation and development. In this study, the anti-atherosclerotic effect of verbascoside was evaluated by establishing an atherosclerosis model based on western diet feeding of apolipoprotein E-deficient mice for 16 weeks. After 12 weeks of administration during the feeding period, the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) in the plasma of mice were significantly decreased, the formation of arterial plaques was delayed, and the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in plasma were alleviated, showing the hepatoprotective effect. In addition, based on untargeted lipidomic analysis, verbascoside stabilized glycerophospholipid metabolism, modulated lipid metabolism disorders and reduced lipid deposition in the liver to achieve the therapeutic efficacy against atherosclerosis by regulating cardiolipin (CL), ether-linked phosphatidylcholine (ether-PC), lysophophatidylcholine (LPC), phosphatidylcholine (PC), oxidized phosphatidylcholine (OxPC), oxidized phosphatidylethanolamine (OxPE), triacylglycerol (TG), sphingomyelin (SM) back to normal levels.