To investigate the intervention effects of Ligustrum robustum extract(SLKDTE) on hyperlipidemia, a strategy combining transcriptomic analysis and experimental validation was employed. By administering the extract to mice concurrently with an 8-week high-fat diet, the pharmacological intervention effects and underlying mechanisms were objectively evaluated. The results showed that SLKDTE could significantly inhibit weight gain caused by a high-fat diet. The content of total cholesterol(TC), triglycerides(TG), low-density lipoprotein cholesterol(LDL-C), glucose(Glu), alanine aminotransferase(ALT), and aspartate aminotransferase(AST) in serum was all significantly decreased, and the level of high-density lipoprotein cholesterol(HDL-C) increased significantly. Moreover, SLKDTE reduced the serum levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6), and lipopolysaccharide(LPS) in mice. The findings indicated that it had the effects of regulating serum lipid levels and inhibiting inflammation. The histopathological results showed that the accumulation of lipid droplets in the liver decreased, and the levels of ALT, AST, TC, and TG in the liver decreased significantly, suggesting that SLKDTE had the alleviating effect on hepatic lipid deposition. The results of transcriptome sequencing and Western blot verification showed that it significantly upregulated the expression of medium-chain acyl-CoA dehydrogenase(ACADM), hydroxyacyl-CoA dehydrogenase β subunit(HADHB), and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase(EHHADH) proteins, promoting β-oxidation of fatty acids. This study preliminarily revealed that SLKDTE could reduce the risk of hyperlipidemia in mice by interfering with key enzymes in the fatty acid degradation pathway. It provides preliminary experimental basis and clues for the subsequent in-depth development and utilization of L. robustum.