Abstract: Objective: To investigate the mechanism by which blueberry extract (BE) improves metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: A MASLD mouse model was established using C57BL-6J mice that were fed a high-fat diet and treated with BE (100, 200, 300 mg/kg/Day) for 16 weeks. Body weight, liver weight, serum total cholesterol, triglyceride, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels were compared across the groups. The hepatic tissue was subjected to histopathological examination. Free fatty acids (FFA) were used to induce a lipid metabolism disorder model in HepG2 cells, followed by BE treatment (10, 20, 40 μg/mL). Cell viability, total cholesterol, and triglyceride levels were compared across groups, and lipid deposition was assessed using Oil Red O staining. Western Blotting was used to analyze p62, LC3, ATG5, Bax, and Bcl-2 expression. Results: BE significantly stabilized mouse body and liver weight and markedly reduced total cholesterol, triglyceride, ALT, and AST levels (P<0.05). BE significantly improved HepG2 survival (P<0.05), and reduced the total cholesterol and triglyceride levels in these cells. Both in vivo and in vitro studies showed that BE significantly elevated LC3 and ATG5 protein expression and downregulated p62 and Bax/Bcl-2 levels (P<0.05) in a dose-dependent manner. Conclusion: BE ameliorates high-fat-diet-induced MASLD by regulating autophagy and apoptosis, thereby improving hepatic lipid metabolism and protecting against liver injury.