Objectives: Dioscorea bulbifera possesses profound therapeutic potential and is commonly used in traditional Indian, African and Chinese medicine. The present study aimed to evaluate the effect of a hydromethanolic extract of Dioscorea bulbifera on the serum lipid profile, lipase, ghrelin, food intake and body weight of high-fat obese Wistar rats. Methods: Thirty (30) male Wistar rats weighing 200 – 250 g were used for the study. Obesity was induced using a formulated high-fat diet for six (6) weeks. They were divided into six (6) groups of five (5) rats each. The negative control received distilled water, while the positive control received a standard antihyperlipidemic drug, simvastatin. Obese rats were treated with hydromethanolic extract of Dioscorea bulbifera at 200 mg/kg and 400 mg/kg for a period of two (2) weeks. Results: The results showed significantly decreased serum total cholesterol (TC), low-density lipoprotein (LDL), lipase, fasting blood glucose and body weight of experimental animals compared to the negative control (P < 0.05), while serum high-density lipoprotein (HDL) and ghrelin were found to be significantly higher in experimental animals compared to the negative control (p < 0.05). There was no significant change in the food intake of the animals. Conclusion: The antiobesity potentials of hydromethanolic extracts of Dioscorea bulbifera may be attributable to their ability to reduce lipase activity while attenuating the lipid profile in high-fat obese Wistar rat models. Therefore, this study considers Dioscorea bulbifera as a potential natural anti-obesity agent with possible anti-lipase activity.