Background: Indomethacin is a non-steroidal anti-inflammatory drug which is known to produce serious adverse effects including ulcerative lesions. Nesfatin-1, is an identified anorexigenic peptide to have antioxidant effects. Objective: This study aimed to investigate the possible ameliorative effect of nesfatin-1 against indomethacin induced gastric ulcer in rats, with exploration of the possible mechanisms underlying this effect. Materials and methods: Twenty four  adult male albino rats were the animal model of this study. Ulcers were induced using oral indomethacin (20mg/kg) daily for 7 days. The rats were randomly assigned to vehicle-treated control group (I), indomethacin-treated (II), and indomethacin-treated for 7 days followed by nesfatin-1 (1ug/kg i.p) daily for 10 days. Assessment of gastric  juice parameters (total acid output, pepsin activity and mucin content),gastric mucosal levels of malondialdehyde (MDA) , tumor necrosis factor –alpha (TNF-alpha) , nitrite and prostaglandin E2 (PGE2) levels were also determined. This in addition to assessment of gastric lesions and histopathologic examination of the gastric mucosa in each group. Results: Nesfatin-1 displayed a significant  ameliorative effect in  gastric lesions induced by indomethacin as indicated by a significant decrease in ulcer index  and improved histopathology, along with a significant  reduction in measured gastric juice parameters .It also reduced both  gastric mucosal MDA and TNF-alpha significantly and increased nitrite and PGE2 levels in this ulcer model. Conclusion: Nesfatin-1 attenuates indomethacin- induced gastric ulcer and potentiates  ulcer healing in the stomach of rats exposed  to chronic administration of indomethacin. This  effect  depended upon decrease in gastric secretion, increase in  nitric oxide and PGE2, besides an antioxidant anti-inflammatory role.