Cucumeropsis mannii (CM) belongs to the melon family and is native to West Africa. There is a paucity of information on its medicinal or nutraceutical potential. Here, we examined the impact of CM in mice that were treated with a normal or a high fat diet (HFD). The CM extracts had a high levels of phenols, flavonoids, ascorbic acid and significant antioxidant activity. Treatment of mice with a HFD diet, led to the memory impairment. However, mice on HFD and received CM, despite increased food intake, showed a decrease in the body weight, locomotion, rearing, grooming, acetylcholinesterase activity and ?-amino butyric acid levels and anxiolysis. Also CM induced a reversal of HFD-induced changes in glucose levels, lipid peroxidation and super-oxide dismutase activity. These data show that CM leads to variable behavioural, biochemical and metabolic effects depending on the diet of animals.