The natural alkaloid evodiamine enhances cholesterol efflux from cultured THP-1-derived macrophages, but whether it has any impact on blood lipids <i>in vivo</i> remains unknown. In this study, the effect of evodiamine on hyperlipidemia induced by a high-fat diet (HFD) was investigated in mice. Intragastric administrations of evodiamine (10 and 20 mg/kg) for 8 weeks resulted in a significant improvement of metabolic lipid profiles by reducing the plasma levels of triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C). Evodiamine also significantly decreased hepatic lipid accumulation and hepatic total bile acids (TBA). Mechanistically, evodiamine increased ATP-binding cassette transporter G1 (ABCG1) mRNA and protein expression and up-regulated peroxisome proliferator-activated receptor gamma (PPARγ) expression in the liver. Taken together, the natural product evodiamine lowers blood lipids in HFD-fed mice likely through promoting the PPARγ-ABCG1 signaling pathway.