Background: Non-alcoholic fatty liver disease (NAFLD) is a serious chronic hepatic disorder with high prevalence globally and commonly coincides with obesity and type 2 diabetes mellitus (T2DM). Dapagliflozin (Dapa), a sodium glucose cotransporter-2 (SGLT2) inhibitor, has an antidiabetic effect through increasing urinary glucose excretion also exerts beneficial effects on metabolic system. The current work aims to assess the possible protective effect of Dapa in hepatic steatosis induced by high-fat diet (HFD) in male albino rats. Methods: 25 male albino rats weighing 200-250 gm were randomly allocated equally into5groups; Control group, HFD group, (Dapa-A, Dapa-B, and Dapa-C groups) received daily dapagliflozin (0.5, 1, and 2 mg/kg, by oral gavage), respectively, for 12 weeks. At the end of experiment, rats were euthanized, the following parameters were measured: body weight (BW), liver weight (LW), and LW/BW ratio, parameters of insulin resistance (IR) assessment, lipid profile, liver enzymes, proinflammatory cytokine: Interleukin 1β (IL1β), profibrotic factors, AMP-activated protein kinase (AMPK), sirtuin1 (SIRT1), hepatic farnesoid X receptor (FXR) and liver-X-receptorα (LXRα), along with assessment of blood pressure. Results: Dapa significantly decreased BW, LW, LW/BW ratio, parameters of IR, lipid profile, liver enzymes, IL1β, LXRα, mean arterial blood pressure as compared to HFD group and significantly increased AMPK, SIRT1, and FXR compared to HFD group. Best values were detected in the dose of 2mg/kg/day that were insignificantly different from control group in most of the parameters. Conclusion: Dapa hasa potential effect against NAFLD confirmed by reduced BW, liver weight along with declined liver enzymes and lipid profile. Furthermore, Dapa treatment was associated with lowered inflammatory response and downregulation of IL1β and LXRα, along with upregulated FXR, AMPK and SIRT1 in liver tissue. The current results give additional insights for the protective potential of Dapa on NAFLD. Keywords: NAFLD, HFD, dapagliflozin, AMPK, SIRT1