Aframomum melegueta is a West African plant well known for its nutritive and medicinal values. The study was undertaken to evaluate the effect of   Aframomum melegueta (AM) aqueous leaf extract on obesity induced by combined Monosodium Glutamate (MSG) and High Fat Diet (HFD) in white albino rats. Obesity was induced in neonates’ rats subcutaneously injected with MSG (2 mg/g and 4 mg/g bwt) and HFD using three models: MSG fed rats, MSG + HFD fed rats and HFD fed rats. Rats were fed till 4 months of age at the end of which plasma insulin and leptin concentrations were estimated Also, Lee index was calculated to evaluate the obesity status in the animals. The activity of AM (200 and 400 mg/kg bwt) and Orlistat (50 mg/kg bwt) was orally administered, in each of the three models, to the obese rats for 45 days. Changes in body weight, blood glucose, insulin and leptin concentrations, liver and plasma lipid profiles, atherogenic and cardiac indices, activity of hormone sensitive lipase were recorded and compared with the controls. Aqueous extract of A. melegueta leaf reduced significantly body weight, atherogenic and cardiac indices, blood glucose, insulin and leptin concentrations, lipid profiles and lipase activity in obese rats in a dose-dependent manner. Interestingly, it was observed that AM extract was more effective than Orlisat in the treatment and management of MSG-induced obesity. Furthermore, histopathological examination of pancreas revealed the alleviating effect of A. melegueta extract. The study thereby suggests A. melegueta leaf as a formidable natural product to develop anti-obesity drug.