No study till date has reported the effect of fractions of Vernonia amygdalina on obese animals as a way of developing novel drugs for the treatment of obesity.To investigate the effect of fractions (F1-F5) from methanol extract of Vernonia amygdalina (VA) on high fat diet induced obese rats.Methanol extract of VA was fractionated using a column. After twelve weeks of obesity induction, forty-eight male wistar rats were randomly distributed into eight groups. Groups A-E received fractions F1-F5; group F received orlistat (positive control); group G received high fat diet (negative control). Following 4 weeks of administration of the fractions, the total cholesterol, triacylglycerol, High Density Lipoprotein Cholesterol (HDL-c), Very Low-Density Lipoprotein Cholesterol (VLDL-c), blood glucose, body weight, relative liver, kidney, spleen and intestinal weights, serum amylase, intestinal amylase, pancreatic lipase activities, insulin, leptin and adiponectin concentrations of the rats were measured.There were significant decreases (P<0.05) in the relative liver weights (3.2 g/100 g), HDL-c (13.99 mg/dL) and adiponectin (0.18 ng/mL) concentrations, no significant differences in the relative kidney (0.67 g/100 g), spleen (0.20 g/100 g) and intestinal weights (5.3 g/100 g) but significant increases (P<0.05) in the VLDL-c (45.78 mg/dl), triacylglycerol (228.93 mg/dL) concentrations, coronary and cardiovascular risk indices (16.10 and 16.36 respectively expressed as ratios), serum and intestinal amylase (264.42 and 120.73 U/L respectively), and serum lipase activities (43.37 U/L), insulin (1.55 ng/mL), leptin (0.027 pg/mL), glucose and body weights of the negative control compared with the positive control. Fractions F4 or F5 positively modulated most of these parameters better than fractions F1 to F3 in a manner that was close to orlistat.Modulation of HFD induced obesity by fractions F4 and F5 suggests their potentials as useful agents for the management of obesity.