Leptin affects insulin secretion and action through either a central or peripheral mechanism. It increases glucose metabolism and energy expenditure. Though overweight and obese individuals have been reported to have high circulating leptin levels, these effects of leptin are not evident. Exercise, on the other hand, has been found to increase glucose uptake in these individuals. This study examined the effect of chronic leptin treatment and exercise on body weight, glucose homeostasis and insulin sensitivity in Sprague-Dawley rats. Eight-week old rats were treated with either intraperitoneal injection of normal saline (Control; n=8), or leptin (60 μg/kg body weight/day; Leptin; n=8), or leptin and exercise (60 μg/kg body weight/day plus running on a treadmill every other day for 30 minutes at a speed of 30 m/min with 10° inclinations; Leptin-exercise; n=8) or exercise only (running every other day for 30 minutes at a speed of 30 m/min with 10° inclinations on a treadmill; Exercise; n=8) for six weeks. Following six weeks of treatment, glucose challenge was performed by intravenous infusion of 100 mg/ml of glucose for 5 minutes. During the protocol, blood was drawn at 0, 5, 10, 15, 20, 25 and 30-min for blood glucose, serum glucose, and serum insulin levels determination. Data were analyzed using One Way ANOVA with post-hoc analysis and expressed as mean ± standard error of mean (SEM). Despite no different in body weight between the groups, leptin group had a slightly higher trend of mean body weight compared to other groups. Glucose clearance was delayed in the leptin group. This delay in glucose clearance might be associated with lower insulin level and action in leptin group. More importantly, exercise reversed the leptin effects by promoting glucose clearance despite a significantly lower insulin peak, indicating increase in insulin sensitivity. In conclusion, six weeks of daily leptin administration resulted in delayed glucose clearance, but concurrent exercise however prevented these effects of leptin by promoting glucose clearance and increasing insulin sensitivity.