Introduction: Peptic ulcer is a defect in the upper gastrointestinal mucosa that extends through the muscularis mucosa into deeper layers of the wall, which occurs because of a mismatch of aggressive and protective factors in the stomach. Considering that until today, the potential contribution of central H3 receptor in affecting gastric acid secretion has not been widely investigated, and its anti-inflammatory function is contradictory, in this study, the gastroprotective effect of betahistine as an antagonist of histamine H3 receptors on cytokine-induced neutrophil chemoattractant-2ɑ (CINC-2ɑ) expression against indomethacin-induced gastric mucosa injury in rats were studied. Methods and Materials:Adult male Wistar rats with weights between 200-250 grams were used for this study. Rats were divided into four groups, randomly; the first group served as control, group 2 was treated with indomethacin (25 mg/kg), Group 3 was pre-treated with betahistine (50 mg/kg) 5 days before indomethacin administration, and group 4: Pre-treated with famotidine (reference drug) (25 mg/kg) 5 days before indomethacin administration.Six hours after indomethacin administration, rats were anesthetized, and their stomach excised. Macroscopic examination of ulcers and wound index assessment with J-score and ascertainment of CINC-2alpha gene expression in Real-time PCR were established. Results: Pretreatment with betahistine (50mg/kg) significantly decreased wound index and CINC-2alpha gene expression (P <0.01) in the stomach of rats. Conclusion:Pre-treatment with betahistine could protect against the gastric damage induced by indomethacin by lowering the expression of CINC-2ɑ. It seems that the gastroprotective action of betahistine is, at least in part, a result of CINC-2ɑ expression being modulated, which prevents inflammation in stomach ulcers.