Introduction: Securigera securidaca seed is used as a hypoglycemic agent in Iranian folk medicine. In this study, potential effect of oral administration of whole seed extract its fractions were investigated on Streptozosin diabetic mice and rats (200 mg/kg, ip). Materials and Methods: In acute study, diabetic mice were received different doses of whole seed extract, its fractions including chloroform, methanol, or mixture of chloroform and methanol, along with glibenclamide (10 mg/kg) and normal saline, by gavage. Blood glucose levels were assessed at baseline and again during 1, 2 and 4 h after gavage. Diabetic rats were received a mixture of chloroform and methanol fraction (30:70) in a dose 500 mg/kg, along with regular and NPH Insulin (30:70), glibenclamide and normal saline, by gavage, two times a day for two weeks. Blood glucose levels were measured at baseline and again after one and two weeks. Blood biochemical measures and liver histology examination were done after two weeks. Results: Acute study showed that chloroform fraction reduced blood glucose level after 1 h wherease methanol fraction and mixture of fractions decreased blood glucose levels toward a normal range, after 4 h. In sub-acute study, no significant change was not observed in blood glucose and biochemical parameters, after administration of fractions. Compared to rats received mixture of fractions, liver cells destruction was lower in groups receiving insulin and glibenclamide. Conclusion: Acute dose of S. securidaca seed could reduce blood glucose by similar mechanism as insulin.