Purpose. Hydroxytyrosol (HT) processes multiaspect pharmacological properties such as antithrombosis and antidiabetes. The aim of this study was to explore the antistherosclerotic roles and relevant mechanisms of HT.Methods. Male apoE(-/-)mice were randomly divided into 2 groups: the control group and the HT group (10 mg/kg/day orally). After 16 weeks, blood tissue, heart tissue, and liver tissue were obtained to detect the atherosclerotic lesions, histological analysis, lipid parameters, and inflammation. And the underlying molecular mechanisms of HT were also studied in vivo and in vitro.Results. HT administration significantly reduced the extent of atherosclerotic lesions in the aorta of apoE(-/-)mice. We found that HT markedly lowered the levels of serum TG, TC, and LDL-C approximately by 17.4% (p=0.004), 15.2% (p=0.003), and 17.9% (p=0.009), respectively, as well as hepatic TG and TC by 15.0% (p<0.001) and 12.3% (p=0.003), respectively, while inducing a 26.9% (p=0.033) increase in serum HDL-C. Besides, HT improved hepatic steatosis and lipid deposition. Then, we discovered that HT could regulate the signal flow of AMPK/SREBP2 and increase the expression of ABCA1, apoAI, and SRBI. In addition, HT reduced the levels of serum CRP, TNF-alpha, IL-1 beta, and IL-6 approximately by 23.5% (p<0.001), 27.8% (p<0.001), 18.4% (p<0.001), and 19.1% (p<0.001), respectively, and induced a 1.4-fold increase in IL-10 level (p=0.014). Further, we found that HT might regulate cholesterol metabolism via decreasing phosphorylation of p38, followed by activation of AMPK and inactivation of NF-kappa B, which in turn triggered the blockade of SREBP2/PCSK9 and upregulation of LDLR, apoAI, and ABCA1, finally leading to a reduction of LDL-C and increase of HDL-C in the circulation.Conclusion. Our results provide the first evidence that HT displays antiatherosclerotic actions via mediating lipid metabolism-related pathways through regulating the activities of inflammatory signaling molecules.