Indomethacin (IND) is a non-steroid anti-inflammatory agent that is known to induce severe gastric mucosal lesions. In this study, we investigated the protective effect of selenium (SEL), grape seed extract (GSE), and both on IND-induced gastric mucosal ulcers in rats. Sprague-Dawley rats (200-250 g) were given SEL, GSE, and both by oral gavage for 28 days, and then gastric ulcers were induced by oral administration of 25 mg/kg IND. Malondialdehyde (MDA), non-enzymatic (reduced glutathione, GSH) and enzymatic (superoxide dismutase, catalase, and glutathione peroxidase) antioxidants, prostaglandin E2 (PGE2) in gastric mucosa, and serum tumor necrosis factor alpha (TNF-α) were measured. Moreover, gastric ulcer index and preventive index were determined. Indomethacin increased the gastric ulcer index, MDA, TNF-α, and decreased PGE2 and non-enzymatic (GSH) and enzymatic (superoxide dismutase, catalase, and glutathione peroxidase) antioxidants. Pretreatment with SEL, GSE, and both significantly decreased the gastric ulcer index, MDA, and TNF and increased antioxidants and PGE2. Histopathological observations confirm the gastric ulcer index and biochemical parameters. Selenium and GSE have a protective effect against IND-induced gastric ulcers through prevention of lipid peroxidation, increase of GSH, activation of radical scavenging enzymes, PGE2 generation, and anti-inflammatory activity. Co-administration of GSE and SEL is more effective than GSE or SEL alone.