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Background: The effect of quercetin on blood glucose levels has been widely studied. However, the mechanism of hypoglycemic effect of quercetin remains unclear. Objective: To elucidate hypoglycemic effect of quercetin, microarray data of GSE38067 dataset have been used to screen Differential Hub Genes (DHGs) by differential expression analysis, weighted gene co-expression network analysis and protein-protein interaction analysis. Methods: Through systematic data mining in this study, the hypoglycemic effect of quercetin was exerted via affecting the gene expression of seven candidate DHGs, especially Cdkn1a and Cd36 genes, to relieve insulin resistance, prevent oxidative damage and protect pancreatic β-cells in streptozotocin (STZ) induced diabetic mice. Result and Conclusion: As a result, this work provides a possible way to fight against diabetes by using quercetin as functional food ingredients or medicine.