Objective(s):To evaluate the gastroprotective potential of zafirlukast against indomethacin-induced gastric ulcers in rats.Materials and Methods:Thirty-two male Wistar rats were included in this study and randomly divided into 4 equal groups (n=8); control (normal) group, indomethacin group, Ranitidine group, and Zafirlukast group. Indomethacin was given as a single oral dose of (20 mg/kg) for the induction of ulcers. Both ranitidine (50 mg/kg) and zafirlukast (20 mg/ kg) were given orally for seven days after inducing the ulcer. All animals were sacrificed by an overdose of anesthesia at the end of the experimental period and their gastric tissues have been collected for histopathological and biological assay. Levels of prostaglandin E2 (PGE2), thiobarbituric acid reactive substances (TBARS), and interleukin 1β (IL-1β ) were measured as well as a histopathological study to evaluate the effect of zafirlukast on gastric tissues.Results:Significant abnormalities were found in both the histological and biochemical parameters of the indomethacin group reflecting the changes seen with gastric ulcers. Significant improvement was found in the Zafirlukast group as reflected by the morphological improvement seen in the gastric tissues. An effect that was associated with an increase in the PGE2 levels along with reductions in IL-1β expression and TBARS concentrations.Conclusion:As per the results of this study, zafirlukast shows promising gastroprotective properties possibly through enhancement of PGE2 levels as well as having anti-inflammatory and anti-oxidant properties.