BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a globally prevalent liver disease, closely linked to the rising incidence of obesity, diabetes, and metabolic syndrome. Dapagliflozin (DaPa), a sodium-glucose cotransporter-2 inhibitor, is primarily prescribed for diabetes management. It has shown potential efficacy in managing MASLD in clinical settings. However, the molecular mechanisms underlying the effects of DaPa on MASLD remain poorly understood. Hence, we aimed to investigate the role of and mechanisms underlying DaPa in MASLD. METHODS: Male diet-induced obese (DIO) C57BL/6J mice were injected with streptozotocin (STZ), followed by a high-fat diet regimen to stimulate metabolic dysfunction. Subsequently, they received DaPa via gavage for 5 weeks. Hepatic lipid accumulation, pathological alterations, inflammatory markers, and liver fibrosis were assessed. RESULTS: DaPa administration reduced liver fat accumulation in DIO mice. Additionally, it decreased oxidative stress and lipid peroxide levels, which was attributed to the upregulation of glutathione and the downregulation of malondialdehyde and reactive oxygen species levels. Notably, DaPa downregulated the inflammatory response and reduced liver fibrosis. CONCLUSIONS: DaPa protects against MASLD by inhibiting lipid accumulation, inflammation, oxidative stress, and liver fibrosis.