The current treatment for diabetic nephropathy (DN) is still limited. NaoXinTong Capsule (NXT) is a Chinese Medicine prescribed to patients with cardiovascular disease. It can also ameliorate metabolic syndromes in patients indicating its anti-diabetic properties. Herein we report the therapeutic effects of NXT on the developed DN. The db/db diabetic mice at ˜12 weeks old, the age with DN at middle/advanced stages, were treated with NXT for 12 weeks. We found NXT treatment reduced diabetes-induced hyperglycemia and dyslipidemia, thereby substantially reduced DN progress. In the kidney, NXT reduced mesangial matrix expansion and glomerulosclerosis by inhibiting extracellular matrix accumulation through activation of matrix metalloproteinase 2/9 and inactivating transforming growth factor β1 expression. NXT reduced podocyte injury by reducing renal inflammation and expression of adhesion molecules. Mechanically, NXT potently activated AMPKα in multiple tissues thereby enhancing energy metabolism. In the liver, NXT increased glucokinase expression and insulin sensitivity by increasing insulin receptor substrate 1/2 and protein kinase B (AKT) 1/2 expression/phosphorylation. In skeletal muscle, NXT activated expression of glucose transporter type 4, AKT, glycogen synthase and peroxisome proliferator activated receptor α/γ. In adipose tissue, NXT reduced fatty acid synthase while activating hormone-sensitive lipase expression. Taken together, our study demonstrates that NXT reduced progress of the developed DN by ameliorating glucose, lipid and energy metabolism, maintaining renal structural and functional integrity. Our study also indicates the potential application of NXT for DN treatment in clinics.