Abstract: To investigate the hypolipidemic effects and antioxidant levels of total flavonoids from seabuckthorn fruit peel and residue, in vitro and in vivo experiments were conducted to examine the hypolipidemic functionality of the purified total flavonoids from seabuckthorn fruit peel and residue (TFSE). The antioxidant activity of TFSE was determined through in vitro experiments, and its binding capacity to three types of bile acids was investigated by simulating the human gastrointestinal environment. This was conducted to evaluate its antioxidant and hypolipidemic effects in vitro. In the in vivo experiment, a high-fat diet-induced hyperlipidemia model was established in C57BL/6J mice, and 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), alanine aminotransferase (ALT), alkaline phosphatase (AKP), and lactate dehydrogenase (LDH) in mice serum. Furthermore, TFSE significantly increased (P<0.05) the superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) levels in mice liver, and significantly decreased (P<0.05) the whilst malondialdehyde (MDA) content. In summary, TFSE would improve the hepatic pathological damage caused by a high-fat diet, showed effective lipid-lowering activity and antioxidant activity. This study would provide a theoretical basis for improving the added value of sea buckthorn peel residue products in Xinjiang.