Liver ischemia/reperfusion (IR) injury is a critical cause of mortality in patients undergoing liver transplantation. Our objective was to assess the protective impact of empagliflozin (EGZ) on IR-induced liver damage in rats and to investigate its potential protective mechanism. A total of 24 male Wistar albino rats were randomly divided into four groups: sham; IR; EGZ (10 mg/kg/day; p.o) and IR + EGZ. Serum levels of aminotransferase ALT and AST, gamma glutamyl transferase GGT and total bilirubin TB were evaluated. Liver samples were used to evaluate oxidative stress indicators, reduced glutathione GSH, malondialdehyde MDA, total nitic oxide NOx and myeloperoxidase MPO, inflammatory mediators as tumor necrosis factor alpha TNF-α and interleukin -33 IL-33, and apoptosis markers, Bcl-2-associated X protein Bax, galactine-9 Gal9 and B-cell lymphoma 2 Bcl2. Hepatic vascular endothelial growth factor VEGF and fibrinogen expressions were determined by Western blot analysis. Immunohistochemical analysis for hepatic SMAD-4 and NF-κB was performed along with histopathological examination. Pretreatment with EGZ significantly ameliorated liver functions and oxidative stress compared to IR injury model. Similarly, the inflammatory cytokines were significantly decreased along with marked decline of the apoptosis biomarkers and a significant decrease of VEGF and fibrinogen expressions. Additionally, SMAD-4 and NF-κB protein expressions were significantly decreased compared to IR group. These results were further supported by improvement liver architecture. Our findings suggested that EGZ has the potentiality to be protective against hepatic IRI.