Mucosal balance impairment, bacterial overproliferation, cytokines, inflammatory mediators are known as responsible for inflammatory bowel disease. Besides known anorexigenic, neuroprotective, and anti-apoptotic effects, the major effect of nesfatin-1 on colitis is unknown. Our aim was to investigate the possible anti-inflammatory effects of nesfatin-1 in acetic acid induced colitis model and the underlying mechanism. Male Sprague-Dawley rats (n=48) were used. The rats were anesthetized by intraperitoneal ketamine (100mg/kg) and chlorpromazine (10mg/kg). For nesfatin-1 and antagonist applications some of the rats were intracerebroventricularly (icv) cannulated. In colitis groups, intrarectally 4% acetic acid solution (1 ml) and 10 minutes later icv nesfatin-1 (0.05 μg/5 μl) or vehicle (5 μl) were administered. Treatments continued for 3 days. In control group physiological saline solution was used intrarectally. In the second part of the study, to identify the underlying effective mechanism of Nesfatin-1, following colitis induction; icv atosiban (oxytocin receptor antagonist, 3 μg/rat) and nesfatin-1 were administered respectively for 3 days. On the fourth day, rats were decapitated and colon tissues were sampled. Macroscopical and microscopical damage scores of distal colon, and colonic tissue malondialdehyde (MDA), glutathione (GSH), myeloperoxidase (MPO), superoxide dismutase, catalase (CAT), luminol and lucigenin chemiluminescence measurements were made. GraphPad Prism 5.0 was used for statistical analysis. All data were expressed as mean ± SEM. Groups of data were compared with Mann-Whitney U non parametric test and Student t-tests. In colitis group, MPO activity, MDA levels, luminol and lucigenin chemiluminescence measurements, macroscopic and microscopic damage scores were increased and antioxidant GSH and CAT levels were diminished compared to control group (p<0.05-0.001). Oxidant damage due to colitis model was decreased with Nesfatin-1 treatment, and the anti-inflammatory effects of nesfatin-1 were observed with alleviated microscopical (p<0.01) and macroscopical (p<0.001) damage scores. Additionally, the increased MPO and MDA levels, luminol and lucigenin chemiluminescence measurements in colitis group were declined with Nesfatin-1 treatment (p<0.05-0.001). Nesfatin-1 might show this effect by inhibiting neutrophil infiltration and by decreasing formation of free oxygen radicals. Atosiban administration alleviated the protective effect of nesfatin-1 from macroscopic, microscopic and oxidant damage parameters and lipid peroxidation (p<0.05-0.001). The results of the study suggest that nesfatin-1 had a protective effect from colitis induction, and the anti-inflammatory and antioxidant effects of nesfatin-1 on colitis might occur via oxytocin receptors.