The present study was designed to investigate anti-ulcerogenic property of ethanolic extract of Desmodium gangeticum (DG) against cold restraint (CRU, 2 hr cold restraint stress), aspirin (ASP, 150 mg/kg orally), alcohol (AL, absolute alcohol 1 ml/200gm) and pyloric ligation (PL, 4 hr pylorus ligation) induced gastric ulcer models in Sprague Dawley rats, and histamine (HST, 0.25 mg/kg) induced duodenal ulcer in guinea pigs. We found that DG at a dose of 200mg/kg, (orally), markedly decreased the incidence of ulcers in all the above models. DG showed significant protection against CRU (68.37%), AL (88.87%), ASP (38.2%), PL (40.63%) and HST (63.15%) induced ulcer models, whereas standard drug omeprazole (OMZ) showed protection index of 83.86, 56.35, 70.31 and 84.21%, respectively in CRU, ASP, PL and HST models. Sucralfate as standard drug showed 92.64% protection in AL model. DG significantly reduced acid secretion 41.61%, whereas OMZ produced 43.13% reduction. Treatment with DG showed increase in mucin secretion by 56.17%, whereas OMZ showed 12.45% increase. Anti-ulcer effect of DG may be due to its cytoprotective effect along with antisecretory activity and could act as a potent therapeutic agent against peptic ulcer disease.