Exposure to ionizing radiation produced radiation sickness that is a collection of short- and long-term complications. The aim of the present study was to investigate the potential neuroprotective effect of melatonin (MLT) on radiation-induced cell death and hippocampus injury. Rats were divided into seven groups namely control, two melatonin treated groups (MLT-1 and MLT-7) treated with melatonin for one and 7 days, two irradiated groups (Rad-1 and Rad7) sacrificed after one and seven days respectively, and two melatonin treated and irradiated groups (MLT-Rad-1 and MLT Rad-7) sacrificed after one- and seven-days post irradiation. Control rats did not receive any treatment. Melatonin treated groups were injected melatonin at a dose of 10mg/kg. Rats in the Irradiated groups, rats were subjected to a single dose of 4Gy γ-radiation from cobalt-60 source. The present results showed that melatonin protected against body weight loss, nestin up-regulation and protected the histological structure of the hippocampus against irradiation. This will enable to the development of radio-preventive strategies for human under radiotherapy as well as occupational and professional exposure to ionizing radiation.