Abstract: Background and Objective: Gastric ulcer is usually accompanied by an imbalance between the pro-inflammatory cytokines and the gastroprotective agents that save the lining of the stomach, the most important of which are antioxidants. This study aimed to explore the potential protective action of grape seed extract (GSE) against indomethacin (IND)-induced gastric ulcer and to compare the results with a standard antiulcer drug, pantozol (Panto). Furthermore, the underlying mechanism will be explored focusing on the oxidative stress and inflammation. Materials and Methods: Gastric ulcer was induced by a single oral dose of IND (30 mg kg–1). Rats were pretreated with Panto (20 mg kg–1), GSE (100 mg kg–1) or both Panto+GSE once daily for 14 days before ulcer induction. Results: Gross evaluation of gastric mucosal lesions showed that Panto, GSE and Panto+GSE pretreatment reduced gastric lesions induced by IND. In addition, pretreatment with Panto, GSE and Panto+GSE before ulcer induction diminished ulceration of surface epithelium and maintained the normal histological structure of gastric mucosa. Ulcer index (UI), total gastric acidity and pH were significantly reduced in rats pretreated with Panto, GSE and Panto+GSE group. Pretreatment with GSE, Panto and GSE+Panto significantly decreased gastric mucosal oxidative stress (malondialdehyde, MDA), serum pro-inflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-6) compared with IND group. In these groups, a remarkable increase in the gastric tissues content of nitric oxide (NO) and prostaglandin (PG) E2 was also detected. Co-pretreatment with GSE+Panto showed a better ulcer healing capacity and compared favorably well with Panto results. Conclusion: These results concluded a gastroprotective effect of GSE against IND-induced gastric ulcer. This could be attributed to its antioxidant and anti-inflammatory actions. Furthermore, a combination of GSE and Panto provoked a better healing effect compared to GSE alone and Panto alone.