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Plantaginis Semen-Coptidis Rhizoma Compound(CQC) was first recorded in Shengji Zonglu. Clinical and experimental studies have reported that both of Plantaginis Semen and Coptidis Rhizoma exerted the effects of lowering blood glocose and lipid. However, the potential mechanism of CQC on type 2 diabetes (T2DM) remain unclear. The main objective of our investigation was to explore the mechanisms of CQC on T2DM based on network pharmacology and experimental research. Streptozotocin(STZ)/high fat diet(HFD)-induced T2DM models in mice were established to evaluate the antidiabetic effect of CQC in vivo. We obtained the chemical constituents of Plantago and Coptidis from the TCMSP database and literature sources. Potential targets of CQC were gleaned from the Swiss-Target-Prediction database, and T2DM targets were obtained from Drug-Bank, TTD, and DisGeNet. A protein-protein interaction (PPI) network was constructed in the String database. The David database was used for gene ontology (GO) and KEGG pathway enrichment analyses. We then verified the potential mechanism of CQC that were predicted by network pharmacological analysis in STZ/HFD-induced T2DM mouse model. Our experiments confirmed that CQC improved hyperglycemia and liver injury. We identified 21 components and gleaned 177 targets for CQC treatment of T2DM. The core component-target network included 13 compounds and 66 targets. We further demonstrated that CQC improve T2DM through various pathways, especially the AGEs/RAGE signal pathway. Our results indicated that CQC could improve the metabolic disorders of T2DM and it is a promising TCM compound for the treatment of T2DM. The potential mechanism may probably involve the regulation of the AGEs/RAGE signaling pathway. [Display omitted] [ABSTRACT FROM AUTHOR]