Peptic ulcer (PU) is a common gastrointestinal disorder that causes damage to the stomach and duodenal mucosal lining. The goal of this research is to look into the impact of empagliflozin (Empa) on peptic ulcers utilizing an indomethacin (Indo) non-diabetic rat model. Adult male Wistar rats were used and divided into three groups. Group I (control group), group II (Indo group) rats received Indo at dose 100 mg/kg/day (p.o) to induce PU, group III (Empa + Indo group) rats received Empa at dose 10 mg/kg (p.o.) daily for 14 days and received 100 mg/kg/day (p.o) of Indo 1 hr before scarification. Before indomethacin was given to any of the animals, pyloric ligation was performed in order to collect gastric juice. PU was assessed by histopathology and inflammatory mediators were measured using the ELISA technique including COX-2, PGE2, pepsin, TNF-α, and NF-κβ. Indo-treated rats had a marked decrease in COX-2 and PGE2. Moreover, Indo-induced PU was inferred from cytoskeletal changes and was attributable to the overexpression of TNF-α, NF-κB, and pepsin. Empa reversed these effects. Conclusion: Empa can alleviate PU induced by Indo through the reduction of COX-2, pepsin, TNF-α, and NF-κβ and elevating gastroprotective PGE2.