Summary This study was carried out to evaluate the radioprotective potential of aqueous extract of seeds of Aframomum melegueta (A.M.) against gamma radiation-induced (6Gy) liver damage in male Wistar rats. Thirty male rats were randomly distributed into six groups of five animals each and aqueous extract of A.M. was administered at a dose of 200 or 400 mg/kg b. wt., orally for 2 weeks prior to irradiation and 4 weeks after irradiation, when they were sacrificed. The hepatic antioxidant status; reduced glutathione (GSH), catalase (CAT) and glutathione peroxidase (GPx) as well as the extent of lipid peroxidation (LPO) were estimated. The activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined and histological examination was carried out. Exposure of animals to irradiation significantly increased LPO levels in comparison with the normal control group, reduced the level of GSH as well as CAT and GPx activity. On the other hand, there was a significant elevation in the activities of serum ALT and AST after irradiation exposure. Administration of aqueous extract of A.M. at a dose of 200 or 400 mg/kg before and after irradiation significantly decreased the elevated levels of LPO, restored GSH level near normal and enhanced CAT and GPx activities as well as significantly decreasing the elevated levels of serum ALT and AST activities. The histological examination and results from this study collectively indicate that aqueous extracts of A.M. could protect the liver from radiation-induced damage probably by enhancing the hepatic antioxidant defense mechanism in rats.