Abstract: To explore the hypoglycemic effect of Moringa oleifera leaf polysaccharide (MOLP) on diabetic mice and its corresponding mechanism, a streptozotocin (STZ)-induced diabetic mouse was modeled. The mice were then divided into groups exposed to low (100 mg/kg·bw), medium (200 mg/kg·bw), and high dosage (400 mg/kg·bw) of MOLP, with a normal blank group, model group and a positive drug group (hydrochloric acid dimethylbiguanide, 200 mg/kg·bw). Eight mice in each group were gavaged for 28 d. Fasting blood glucose, serum glycated protein, serum insulin, hepatic/myocardial glycogen and other biochemical indexes were determined. Additionally, the key genes of glucose metabolism, including liver X receptor (LXR), pancreatic-duodenal homeobox-1 (PDX-1), glucokinase (GK), phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), glucose transporter type 2 (GLUT2) and insulin receptor substrate 1/2 (IRS1/2) were measured in the liver and the pancreas. Furthermore, the mice's liver and pancreas tissues in each group were stained with HE to observe their histomorphology. The results showed that MOLP exhibited a significant hypoglycemic effect and a dose-response relationship. The level of blood glucose reduction in the MOLP high-dose group (400 mg/kg·bw) was closest to that of the positive drug group. The underlying mechanism was that the significantly upregulated expression of LXR and PDX-1 ameliorated the glucose metabolism disorders in diabetic mice by regulating the expression of their downstream genes including PEPCK, G6Pase, GK, GLUT2 and IRS1/2 mRNA. This regulation facilitated the improvement of the damaged liver and pancreatic tissues, increased serum insulin and hepatic glycogen content and ultimately resulted in a hypoglycemic effect.