Abstract: In vitro and in vivo experiments were conducted to investigate the lipid-lowering effect and antioxidant level of total flavonoids from sea buckthorn peel residue (TFSE). To assess the antioxidant and lipid-lowering effects of TFSE, the in vitro study simulated the gastrointestinal environment by evaluating its antioxidant activity and binding capacity with three bile acid salts. In the in vivo experiment, a high-fat diet-induced hyperlipidemia model was established in C57BL/6J mice. Then, TFSE was administered orally to compare its effects on body weight, serum, hepatic lipid levels, liver function indicators, and oxidative indicators. Then, histopathological observations of the liver tissue were completed. The in vitro study showed that TFSE exhibited strong scavenging abilities against DPPH and ABTS⁺ radicals, with IC₅₀ values of 5.20 and 10.24 μg/mL, respectively, thus indicating effective antioxidant activity. Moreover, TFSE showed strong binding capabilities with sodium cholate, glycocholate, and taurocholate, with IC₅₀ values of 11.11, 2.61, and 3.50 mg/mL, respectively, thus highlighting its binding solid capacity with bile acids. Results of the mice experiments showed that, compared to the model group (HFD), the L-TFSE and H-TFSE groups showed inhibited body weight gain, whilst (P<0.05) total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels in serum and liver were significantly decreased. At the same time, significantly increased (P<0.05) high-density lipoprotein cholesterol (HDL-C) levels and significantly decreased (P<0.05) levels of aspartate aminotransferase (AST) were noted. In addition, alanine aminotransferase (ALT), alkaline phosphatase (AKP), and lactate dehydrogenase (LDH) were noted in mouse serum. Furthermore, TFSE significantly increased (P<0.05) the superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) levels in mouse liver, whilst malondialdehyde (MDA) content was significantly decreased (P<0.05). These results indicate that TFSE improves hepatic pathological damage caused by a high-fat diet, showed effective lipid-lowering activity, and enhanced antioxidant activity. This study provides a theoretical basis for improving the added value of sea buckthorn peel residue products in Xinjiang.