Background:Diabetes mellitus (DM) is a chronic disease caused by inherited or acquired deficiency in insulin secretion and by decreased responsiveness of the organs to the secreted insulin. Recently, some medicinal plants have been reported to be useful in diabetes treatment. Cleome droserifolia (Samwah) having a long history in Egyptian folk medicine for treatment of diabetes mellitus. Aim of the work:The aim of the present study was to evaluate the possible antihyperglycemic property of Cleome droserifolia extract (CDE) and its antioxidant mechanism in alloxan induced diabetic rats. Material and Methods:This study was performed on thirty male albino rats of Sprague Dawely strain with an average body weight of 100-110g. Animals were divided into three groups (ten/cage), control untreated group, diabetic group and diabetic group treated with plant extract that was given orally (28.5 mg/kg body wt. twice/ day). Results: Results showed marked decline in levels of serum insulin, body weight, total proteins, albumin, globulin and high density lipoprotein cholesterol (HDL). These are accompanied with marked elevation in levels of fasting blood glucose, HOMA-IR, AST, ALT, GGT, urea, creatinine, uric acid, serum total lipids (TL), total cholesterol (TC), triacylglycerols (TG), low density lipoprotein cholesterol (LDL), very low density lipoprotein cholesterol (VLDL) and ratios of TC/HDL and LDL/HDL (risk factors) in diabetic rats as compared to the corresponding controls. While the daily administration of diabetic rats with CDE showed significant amelioration in most of these parameters. Conclusion: It could be concluded that CDE treatment exerts a therapeutic protective nature in diabetes by decreasing oxidative stress and pancreatic β-cells' damage which may be attributed to its antioxidative potential and antidiabetic property.