This study investigates the effect of oral administration of an aqueous Enicostemma littorale whole plant extract on antioxidant defense in alloxan-induced diabetes in rats. A significant increase in blood glucose and increased concentration of thiobarbituric acid reactive substances (TBARS) and hydroperoxides (HP) in liver, kidney and pancreas were observed in alloxan diabetic rats. Decreased concentration of reduced glutathione (GSH) and decreased activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) were also observed in these tissues of diabetic rats. Oral administration of aqueous E. littorale whole plant extract (1 and 2 g/kg) to diabetic rats daily for 45 days significantly decreased blood glucose, TBARS, HP and increased GSH, SOD, catalase and GPx. E. littorale extract at the dose of 2 g/kg was more effective than 1 g/kg. Insulin (6 units/kg) administration to diabetic rats for 45 days brought back all the parameters to near normal status.