INTRODUCTION: Severe local and systemic tissue injury develop during reperfusion, which is a period during which arterial blood flow and tissue oxygenation are re-established. In this study, we aimed to investigate the anti-inflammatory, antioxidant and protective effects of nesfatin in IR damage developing in liver. MATERIAL AND METHODS: Twenty-four male Wistar-Albino rats were divided to three groups which contained eight rats in all groups. The rats were subjected to 30 minutes of hepatic pedicule occlusion followed by 2h of reperfusion to induce I/R damage. Nesfatin1 (10 µg/ kg) was administered, 30 min prior to ischemia and immediately before the reperfusion period. RESULTS: The findings showed that while the blood levels of AST, ALT and LDH were markedly elevated in the I/R group, they returned to normal levels upon treatment in the Nesfatin group. While IL-1 α, IL-1β, IL-6, TNF-α and IFN- γ levels in blood and tissue were lower after therapy in the Nesfatin group compared to the I/R group, statistically significant decreases were only noted in IL-1β, IL-6, TNF-α and IFN- γ levels. TAS levels increased in the treatment group, while upon nesfatin treatment statistically significant decreases were noted in TOS and OSI levels. Histopathological investigations also showed statistically significant decreases in Bax and Caspase-3 staining intensity and the number of stained cells in the Nesfatin group. CONCLUSION: The nesfatin has antioxidant activity and anti-inflammatory effect on improvement of liver functions and histopathological findings in liver ischemia and reperfusion injury.