This study aims to investigate the mechanism of Citrus aurantiifolia extract (CAE) in the treatment of type 2 diabetes mellitus (T2DM) based on the network pharmacological analysis and in vivo experiments. Ultra-high performance liquid chromatography was used to analyze the main components in CAE, and the contents of flavonoids such as hesperidin, naringenin, nobiletin and tangeretin were quantitatively detected. The network pharmacology was employed to predict the potential signaling pathways involved in the treatment of T2DMwith CAE. The T2DM model was induced by high-fat diet combined with streptozotocin. The effect of CAE on T2DM was verified through animal experiments to preliminarily validate the prediction results of network pharmacology. The results showed that the contents of hesperidin, naringenin, nobiletin and tangeretin in CAE were 5.791, 0.112, 0.523 and 0.498 mg/g, respectively. It was predicted that these four components had 172 potential targets for the treatment of T2DM, with 10 key targets. The GO and KEGG enrichment analysis results obtained 251 pathways, mainly involving lipid and atherosclerosis, endocrine resistance, and advanced glycation end products-receptor for advanced glycation end product (AGE-RAGE) signaling pathway in diabetic complications. The experiments on T2DM mice models demonstrated that CAE could significantly reduce the levels of blood glucose, serum low-density lipoprotein, total cholesterol, creatinine, and blood urea nitrogen in T2DM mice, and significantly increase the level of serum high-density lipoprotein. The RT-qPCR experiments showed that compared with the T2DM group, the expression of protein kinase B (AKT) mRNA was significantly increased, while the expression of glycogen synthase kinase-3β (GSK3β) mRNA was significantly decreased. This study preliminarily indicated that CAE might regulate the AKT/GSK3β pathway through the main components such as hesperidin, naringenin, nobiletin and tangeretin, thereby exerting the effects of regulating disordered glucose and lipid metabolism and treating T2DM.