THE PRESENT study aims at assessing the role of di-indolylmethane (DIM), a metabolite of indole-3-carbinol, in mitochondrial damage, inflammation, apoptosis, and alteration of serotonin metabolism in the cerebral cortex of young (4± 1month-old) and aged rats (22±1 month-old) exposed to gamma-radiation. The rat's whole body was exposed to 8 Gy administered in 2 doses of 4 Gy at 2weeks interval. DIM (45 mg/kg body- weight) was given to rats by gavage 3 h after the 1st radiation-dose, daily till the 2nd dose and 2 weeks after the 2nd dose. The animals were sacrificed 24 h after the last dose of DIM. In young and aged rats, irradiation induced mitochondrial damage evident by significant decreases of adenosine triphosphate (ATP), and mitochondrial nitric oxide synthase (mtNOS) associated with significant increases of malondialdehyde (MDA), protein carbonyl (CO), and 8-hydroxy-2-deoxyguanosine (8-OHdG), markers of lipids, proteins and DNA oxidation, respectively. Irradiation also induced significant increases in the inflammatory markers, tumor necrosis factor-alpha (TNF-α) and active microglia (CD14) and the apoptotic markers cytochrome c and caspase-3. Alteration in serotonin metabolism was evident by significant decreases of serotonin accompanied by significant increases in the activity of its metabolizing enzyme monoamine oxidase (MAO). Nevertheless, by comparing the biochemical variations occurring in the cerebral cortex of young and aged rats, the changes were generally more pronounced in young rats. DIM significantly reduced the mitochondrial damage, and improved the inflammatory and apoptotic responses and serotonin metabolism in young and aged rats. It could be concluded that age is an important risk factor to consider upon exposure to ionizing radiation during therapy or diagnosis. DIM may exert a beneficial impact on irradiation-induced brain injury in young and aged rats.