To study the mechanism of the root of Averrhoa carambola L.(RAC) in the treatment of diabetic kidney disease (DKD) based on network pharmacology.The active components of the RAC and the targets for treatment of DKD were screened and predicted by utilizing PubChem Search,Chemspider,Swiss target prediction and Genecards database.Cytoscape was used to construct the active components-target network map.The protein interaction network map was constructed by String database and the core targets were screened out by CytoHubba.Next,GO and KEGG analyses were conducted by WebGestalt.Finally,key screening targets and signaling pathways were primary validated by animal experiments.A total of 24 active ingredients were obtained,and 59 common targets for ingredients and diseases were screened.Further network analysis showed that the main active ingredients included 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione,cuneataside C,prunasin and daucosterol.The key targets were MMP9,MMP2,EGFR,FGF2,STAT3,MAPK1,VEGFA,and CASP3.In addition,regulation key KEGG signal pathways involved AGE-RAGE signaling pathway,Relaxin signaling pathway,insulin resistance signaling pathway and hypoxia-inducible factor signaling pathway.Cystatin C (CysC) and HE staining suggested that the extract of RAC could improve renal function in diabetic mice.Western-blot showed that the extract of RAC played an important role in preventing and treating DKD by reducing TGFβ1 and NF-κB proteins associated with the AGE-RAGE signaling pathway. In summary,the RAC plays a role in preventing and treatment DKD through multi-component,multi-target,and multi-pathways.