This study aimed to evaluate the effect of Wogonoside (Wog), a flavonoid monomer, on hyperlipidemia and explore its possible mechanisms. APOE -/- mice were used to establish the animal model of hyperlipidemia by feeding the high-fat diet (HFD). The serum level of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA), oil red O staining, and real-time PCR assay. The oxidative stress was measured by ELISA assay. Immunoblot assay and ELISA assay were used to detect the mechanism of Wogonoside on hyperlipidemia. We found that Wogonoside ameliorated lipid metabolism disorders in ApoE -/- mice induced by HFD (P<0.01). Wogonoside also ameliorated HFD-induced inflammation in ApoE -/- mice (P<0.01). Wogonoside ameliorated oxidative stress in HFD-induced ApoE -/- mice (P<0.01). Further study showed that Wogonoside improved HFD-induced hyperlipidemia and inflammation by upregulating SIRT1 expression (P<0.01). These results suggested that Wogonoside has the potential to be used as a promising approach for the intervention of hyperlipidemia.