The small intestine displays numerous morphological and functional alterations after exposure to ionizing radiations. Oxidative stress and changes in monoamines levels may contribute toward some of these alterations. The objective of the current work is to evaluate the efficacy of lycopene on radiation-induced damage in the small intestine. Lycopene (5 mg/kg BW) was given to male albino rats, via gavages for 7 days before whole body exposure to gamma ray (6 Gy). Irradiated animals, sacrificed 7 days after irradiation, showed sloughing villi, ulcers, and ruptured goblet cells, shrinkage of submucosa layers, more fibers and fibroblasts. Histopathological changes were associated with a significant increase in thiobarbituric acid reactive substances (TBARS) and alteration in xanthine oxidoreductase system (XOR). In parallel, significant decreases in reduced glutathione (GSH) content, superoxide dismutase (SOD) and catalase (CAT) activities were recorded. Gamma irradiation has also induced a significant decrease in the level of monoamines: serotonin (5-HT), dopamine (DA), norepinephrine (NE), and epinephrine (EPI) associated with an increase in monoamine-oxidase (MAO) activity. Lycopene pretreatment has significantly improved the oxidant/antioxidant status, which was associated with significant regeneration of the small intestine, and improved monoamines levels. Based on these results, it is concluded that lycopene may protect the small intestine against radiation-induced damage.