Peptic ulcer disease (PUD) is increasing gradually in India as well as worldwide. Excess use of non-steroidal anti-inflammatory agents (NSAID) and lifestyle factors cause gastric mucosal damage. This study was designed to search out the gastro-protective efficacy of hydromethanolic extract of Ayapana triplinervis on different graded ulcers. Mild to severe grade of gastric ulcer has been developed by oral administration of IND at the doses of 10mg, 20mg and 40mg/kg body weight for 15 days. Gastric ulcer were assessed by elevation of ulcer score, ulcer index, pepsin activity and gastric volume in IND-treated groups in respect to control group. Tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) levels were elevated in IND-treated groups in respect to control due to withdrawal of prostaglandin and cyclooxygenase (COX-2) enzyme induced suppression. Significant protection in the levels of these ulcerogenic parameters were observed after the treatment of Ayapana triplinervis (200mg/kg) when compared with the standard drug omeprazole (20mg/kg). The important antioxidant enzymes activities were decreased but lipid peroxidation levels elevated in all the ulcerated groups(p<0.05). Gastricoccult test was positive in 40mg IND-treated group. Glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) activities in serum measured for toxicity assessment. All the parameters that altered in ulcerated groups were significantly protected towards the control level after Ayapana triplinervis or omeprazole treatment. This significant protective efficacy observed in histopathological evaluation of gastric tissue. Ayapana triplinervis significantly protect the mild, moderate and severe grade ulcers by its antioxidant activity and withdrawal of IND-induced suppression of prostaglandin and COX-2 levels.INTRODUCTION: Gastric ulcer (GU) is a major public health burden in the present century 1 with a high morbidity of about 5-10 %. Annually 200,000 people are hospitalized with the diagnosis of ulcer and the financial cost of the treatment of this disease reaches about 4 billion dollars 2 .