Diabetic nephropathy (DN) is a common disease, and patients often do not have satisfactory treatments. We investigated therapeutic effects of Fuxin Granules(FX) on DN and potential molecular mechanisms. We orally administered doses of FX to db/db mice for 10 weeks and measured total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol. H&E, PAS, Masson, and Oil Red O staining were used to observe the structure of kidneys and calculate indices of kidney function. We used pharmacological analysis to investigate potential mechanisms of FX. Relative mRNA and protein levels in the TGF-β1/Smad, TGF-β1/Smad, and VEGF/VEGFR2 pathways were examined. TC, TG, and LDL-C were markedly reduced, lipid accumulation was low, fibrosis reduced, kidney atrophy improved, kidney lipid droplet number significantly reduced, and glomerular filtration function improved by FX treatment. Multi-channel therapeutic effects in DN through the TGF-β1/Smad and VEGF/VEGFR2 signaling pathways occurred, and FX substantially reduced expression of TGF-β1 in the glomeruli. FX significantly inhibited TGF-β1, Smad2/3 total protein levels, Smad2/3 phosphorylation mRNA levels of TGF-β1, Smad2, and Smad3. eNOS, VEGFA, and VEGFR2 expression was regulated, levels of VEGFA and VEGFR2 were decreased, and FX increased eNOS. FX ameliorated symptoms of DN, resulting in marked improvement in hyperglycemia and hyperlipidemia and optimized structure and function of kidneys in db/db mice. FX efficacy was associated with the TGF-β1/Smad and VEGF/VEGFR2 signaling pathways. We verified this potential mechanism and hope that this study will provide benefits for the clinical treatment of DN.