BACKGROUND: Diabetic kidney disease (DKD) represents the primary aetiological factor in end-stage renal disease, wherein lipid metabolism disorders contribute to the progression of DKD. Baicalin, a composition from Scutellaria baicalensis, has exhibited the potential to mitigate lipid metabolism disorders of DKD, but the precise mechanisms remain unclear. METHODS: High-fat-diet (HFD)/streptozotocin (STZ)-induced DKD mouse model was established to appraise the effects of baicalin on renal function, dyslipidemia, and renal ectopic lipid deposition. The effects of baicalin on lipid accumulation in vitro were assessed in tubular epithelial cells derived from mice (TCMK-1) treated with palmitic acid (PA). The potential targets of baicalin were identified by drug affinity responsive target stability (DARTS) -LC/MS. The impact of the identified target on lipid metabolism was elucidated in TCMK-1 cells through both knockdown and overexpression experiments. RESULTS: The findings indicated that baicalin effectively mitigated dyslipidemia and renal ectopic lipid deposition in the HFD/STZ-induced DKD mouse model. FK506-binding protein 51(FKBP51) was identified as an endogenous target of baicalin, with the Tyr113 residue playing a crucial role in the binding interaction. Additionally, FKBP51 knockdown brought about intracellular lipid accumulation, but FKBP51 overexpression was found to effectively counteract the lipid accumulation induced by PA. Further investigation revealed that FKBP51 regulates lipid accumulation through the Tyr113 residue. Notably, the lipid-lowering effect of baicalin was diminished following FKBP51 knockdown. CONCLUSION: This study first identifies that FKBP51 is beneficial for lipid metabolism homeostasis in DKD and suggests baicalin as an effective molecule for targeting FKBP51 in the treatment of lipid metabolism disorders associated with DKD.