Effects of red raspberry extract (RRE) intake on hyperlipidemia mice induced by high-fat diet (HFD) were investigated in this study. After intragastric gavage of RRE for 8 weeks, the body weight and the adipose tissue mass of mice in RRE administration groups significantly (p < 0.05) decreased compared to the group without RRE treatment. RRE treatment significantly (p < 0.05) lowered triglyceride and total cholesterol levels of hyperlipidemia mice. Pparα, Hmgcr, Ldlr, Cyp7a1, Acsl3, Pnpla2 and Pin4 were confirmed as the regulatory genes by transcriptome analysis and qRCR validation. According to KEGG pathway analysis, target genes such as Cyp7a1 and Pin4 were further regulated by the activation of PPARα resulting from RRE supplementation. Meanwhile, liver cholesterol synthesis and conversion were inhibited by the expressions of Hmgcr and Cyp7a1 genes regulated by RRE intake, and Ldlr gene was down-regulated to limit the transport of cholesterol. In addition, RRE treatment could accelerate the conversion from triglyceride to fatty acid. To conclusion, RRE intake would be a protection against diet-induced hypertriglyceridemia. Display omitted •RRE supplementation attenuated hyperlipidemia and oxidative stress in the HFD mice.•RRE intake regulated PPARa expression to further ameliorate lipid metabolism disorder.•RRE intake reduced Hmgcr expression resulting in lower cholesterol.•RRE treatment could accelerate the conversion from triglyceride to fatty acid.