Diabetes Mellitus (DM), especially type II; represents a major health problem in Saudi Arabia, due to the dramatic changes in the lifestyles of Saudi population. As per the report of World Health Organization (WHO) for the occurrence of diabetes, Saudi Arabia ranked the second in the Middle East and seventh in the world. The increasing trends of diabetes in Saudi Arabia are more worrying in the last few years. Type II DM is generally characterized by peripheral insulin resistance and relative insulin deficiency. Quercetin is a natural flavonoid which belongs to a group of natural substances with variable phenolic structures, found naturally in vegetables, fruits and especially in high amounts in onions, apples, tea and grape juice. Self-emulsifying drug delivery system (SEDDS) were prepared following the component ratios. Then, the Quercetin was dissolved and the components were mixed and heated at 37 ºC until the drug perfectly has dissolved. The mixture prepared stored at room temperature. The aim of this study was to optimize concentration of Quercetin leading to efficient decrease in blood glucose level in streptozotocin induced diabetes among the treated rats as compared to the reference drug e.g. glibenclamide. The results showed that the blood glucose lowering activity of flavonoid compounds may be due to stimulating β-cells to release more insulin. The comparative analysis of natural flavonoids showed that the Quercetin was more effective anti-diabetic and hypoglycemic compound.