To explore the potential molecular mechanism of Lipi Jiangzhuo Formula(LPJZF) in treating type 2 diabetes mellitus(T2DM).Methods:Firstly，network pharmacology was employed to screen the active components and targets of LPJZF.The T2DM-related targets(differentially expressed genes) were retrieved from the Gene Expression Omnibus.The protein-protein interaction network of the targets shared by LPJZF and T2DM was established to predict the key targets.Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were performed to predict the pathways involved in the treatment of T2DM with LPJZF.The rat model of T2DM was treated with LPJZF，and proteomics was used to identify the differentially expressed proteins.Then，KEGG and GO enrichment analyses were conducted to predict the potential mechanism of the treatment.Finally，the binding affinity between key potential targets and active components was verified by molecular docking.Results:A total of 63 compounds and 135 targets of LPJZF against T2DM were screened out，and 964 differentially expressed proteins were identified to be involved in the treatment.The phosphatidylinositol 3-kinase/protein kinase B(PI3K-AKT)，mitogen-activated protein kinase(MAPK)，nuclear factor kappa-B(NF-κB)，and forkhead box O(FoxO) signaling pathways were predicted as the key pathways in the treatment of T2DM with LPJZF.Molecular docking results revealed that cyclin-dependent kinase 2(CDK2)，epidermal growth factor receptor(EGFR)，tumor protein P53(TP53)，heat shock protein 90 kDa alpha class A member 1(HSP90AA1)，and mouse double minute 2(MDM2) possessed good affinity with baicalein，formononetin，kaempferol，wogonin，β-sitosterol，and stigmasterol in LPJZF.Conclusion:LPTZF can ameliorate insulin resistance and promote the regeneration of pancreatic β cells，serving as an effective prescription for treating T2DM.