Moutan Cortex (MC), a well-known medicinal herb and distributed in multiple regions of China, has been found to be benefical for improving diabetic nephropathy (DN). The geoherb one worked particularly well with specific structural composition of components (SCC). However, whether its better efficacy of geoherb MC than others on DN was attributed to SCC was still unclear. Medicinal plants of MC were collected from ten regions of China, including Gansu, Chongqing, Shandong, Sichuan, Zhejiang, Hunan, Guizhou, Hebei, Henan and Anhui provinces, which were classified for three categories by cluster analysis. HPLC analysis demonstrated that the content and structural composition of 13 compounds were discrepancy. Principal component analysis (PCA) showed six compounds including oxypaeoniflorin, paeoniflorin, trigalloyl glucose, pentagalloyl glucose, benzoylpaeoniflorin and paeonol were the main contributors to its anti-DN activity via increasing superoxide dismutase (SOD) activity, decreasing malondialdehyde (MDA) content, reducing IL-6 and MCP-1 levels in vitro. The results of advanced glycation end products (AGEs)-induced HBZY-1 cells and STZ-induced DN rats showed a significant efficacy difference among MC from ten regions on catalase (CAT), glutathione peroxidase (GSH-Px) activities, intercellular adhesion molecule-1 (ICAM-1), transforming growth factor-β1 (TGF-β1) and fibronectin (FN) protein expression in vivo and in vitro. The recombination of SCC in Hebei MC (worst efficacy) to Anhui MC (best efficacy) showed a similar efficacy. The results demonstrated that the efficacy of MC was closely related to its SCC. Our findings provide evidence for the importance of SCC in quality control about Chinese materia medica and also provide an novel insight into the better efficacy of geoherb one.