Aim: The study was designed to evaluate the efficacy of ethanolic extract of Benincasa hispida (EEBH) and its active fraction (AFBH) on high fat diet fed rats. Methods: Male wistar rats (200±10g) were divided into five groups of 6 rats. Group I (Normal control), Group II (High fat diet(HFD), Group III (HFD+300mg/kg ethanolic fruit extract), Group IV (HFD+100mg/kg active fraction from ethanolic fruit extract) and Group V (HFD+25mg/kg Orlistat (drug control). After induction of High fat diet, Physical parameters such as body weight, organ weight, fat pad weight, anthropometric parameters were measured. Biochemical parameters such as serum lipid profile, Glucose, insulin, Homeostatic insulin resistance (HOMOIR), Free fatty acids, Phospholipids, homocysteine, apolipoprotein-B(Apo-B), leptin and adiponectin levels were analysed. Enzyme parameters such as Aspartate transaminase (AST), Alanine transaminase (ALT), Alkaline phosphatase (ALP), Lactate dehydrogenase (LDH), Creatinine kinase (CK) and lipase were analysed. Histopathological changes in the adipose tissue were identified using haemotoxylin eosin stain and similarly histopathological changes in the liver were identified using haemotoxylin eosin stain and oil red O staining. Results: Active fraction of Benincasa hispida showed better result in reducing lipid levels such as cholesterol and Triglycerides (TG), Low density lipoprotein (LDL), free fatty acids, Phospholipids, Insulin, HOMO-IR, leptin and enzyme levels. Homocysteine and apolipoprotein B (Apo-B) was an important cardioprotective marker. These parameters also were reduced in AFBH and EEBH treated groups, EEBH and AFBH increases HDL and adiponectin levels, when compared with HFD fed groups. Antilipidemic activity was observed with AFBH. © 2016, International Journal of Pharmaceutical and Clinical Research. All rights reserved.