Moutan Cortex terpene glycoside is derived from the dried root bark of Paeonia suffruticosa Andr. in the Paeoniaceae family, which holds significant value as a traditional Chinese medicine. This study investigated that Moutan Cortex terpene glycoside (MCTG) improved diabetic kidney disease (DKD) by targeting sirtuin 1 (SIRT1) mediated autophagy pathway. Mechanistic insights were gained using DKD model rats and human umbilical vein endothelial cells (HUVECs) to delineate how MCTG operated in the treatment of DKD. Furthermore, network pharmacology was used to identify the primary metabolic pathways affected by MCTG, with key targets being confirmed through polymerase chain reaction (PCR), Western blot, Transmission electron microscope, immunofluorescence staining and monodansylcadaverine (MDC) staining. Finally, small interfering RNA transfection testified SIRT1 in advanced glycation end-products (AGEs)-induced HUVECs injury. MCTG effectively decreased blood glucose rise in DKD rats and reduced levels of cytokines and biochemical indicators. Network pharmacology revealed that metabolism was the main pathway of Moutan Cortex, and the main targets were verified by PCR and protein experiments. Based on these results, we found that Moutan Cortex could improve DKD and SIRT1 was a potential target. Furthermore, knockdown of SIRT1 attenuated AGEs-induced the expression of Beclin 1 and microtubule-associated protein 1 light chain 3 Ⅱ/Ⅰ(LC3 Ⅱ/Ⅰ) in HUVECs. In summary, this study demonstrated that Moutan Cortex could alleviate DKD via down-regulating SIRT1-mediated autophagy pathway.