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Exposure of biological materials to ionizing irradiation causes accumulation of reactive oxygen species. The current study aimed to investigate whether melatonin or carnosine could provide protection against irradiation-induced small intestinal damage. Forty Wistar albino rats were divided into five groups. Melatonin, carnosine, and combination of carnosine and melatonin were injected into rats in the third, fourth, and fifth groups, respectively. Rats were injected three times every 48 hours. All groups, excluding the control group, were exposed to a dose of 8 Gray whole body gamma irradiation one hour after the second injection. It was determined that irradiation caused degenerative changes in the intestinal tissues, reduced PCNA (proliferating cell nuclear antigen) -positive cell number, and increased caspase-3- and TNF-α (tumour necrosis factor alpha) -positive crypt cell numbers. Results obtained from antioxidant-treated groups were similar to those from the control group. Lipid peroxidation and protein carbonyl levels as well as superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, myeloperoxidase, lactate dehydrogenase and xanthine oxidase activities were increased. However, catalase, sodium potassium ATPase activities and glutathione levels were decreased in the irradiated group of animals. Treatment with antioxidants reversed these changes. It is suggested that exogenous melatonin, carnosine, and melatonin+carnosine combination exhibit protective effects against irradiation-induced small intestinal damage.