Abstract: To study the protective effect of phloretin against renal injury in mice with type-2 diabetic nephropathy and determine its potential mechanism at the molecular level, mice were randomized into a normal control group, diabetes model group, positive drug group (metformin, 500 mg/kg), and low-, medium-, and high-dose phloretin groups (100, 200, and 400 mg/kg·d, respectively). After successful modeling, mice in each group were administered the corresponding drugs via the intragastric route. Kidney hypertrophy index and renal pathomorphological changes were observed after 12 weeks. Blood urea nitrogen (BUN), serum creatinine (Scr), urine β2-microglobulin, serum interleukin (IL)-1β and IL-18 levels were determined. Malondialdehyde (MDA) level, glutathione peroxidase (GSH-Px) activity, and nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) pathway-related protein expression in renal tissues were also determined. Compared with the model group, the medium- and high-dose phloretin groups showed a significant decrease in the kidney hypertrophy index of mice (P<0.01). An obvious reduction in glomerular volume was determined using Hematoxylin and Eosin staining and Masson staining, and a significant decrease in mesangial proliferation and an apparent alleviation in glomerular and renal interstitial fibrosis were noted. Significant reductions in BUN, Scr, IL-1β, and IL-18 levels in the blood, in MDA levels in renal tissues, and in the protein expression of α-smooth muscle actin, Collagen I, NLRP3, IL-1β, and Gasdermin D were noted (P<0.05 or P<0.01). A significant increase in GSH-Px activity and in the expression of Nrf2, HO-1, and E-cadherin in renal tissues (P<0.05) was also founded. The results indicated that phloretin could protect renal function and alleviate renal fibrosis in mice with type-2 diabetic nephropathy. Its mechanism may be related to the regulation of the Nrf2/HO-1/NLRP3 pathway to improve oxidative stress and alleviate the inflammatory response.