To investigate the protective effect of quercetin on diabetic nephropathy and to explore its possible mechanism. Type 2 diabetes mellitus rat model was established by feeding high-carbohydrate-fat diet and injecting with streptozotocin. At 72 hour after injection, blood samples were collected from the tail veins of all rats. Those rats with blood glucose level ≥ 16.7 mmol/L were considered as the diabetes model been successfully established. The model rats were randomly divided into type 2 diabetic group (group DM, n = 9) and quercetin group (group QUE, n = 9). Other rats were used as normal controls (group NC, n = 8). All rats were performed by intragastric administration for 8 weeks. At the end of experiment, the rats were sacrificed and fasting plasma glucose (FPG), fasting insulin(FIns), serum creatinine (SCr), blood urea nitrogen (BUN), TG, TC, LDL-C, 24 h urine protein (24 h UP), and kidney index (KI) were evaluated. Pathological changes of kidney were observed by periodic acid-silver methenamine (PASM). The expressions of ubiquitin and NF-κB p65 on glomeruli were examined by immunohistochemical method, and its association with the incidence of proteinuria was analyzed. In groups DM and QUE, the level of FPG [(25.45 ± 1.23) mmol/L and (19.99 ± 1.20) mmol/L], FIns [(25.67 ± 2.58) mU/L and (19.29 ± 1.80) mU/L], SCr [(44.00 ± 2.53) µmol/L and (34.43 ± 2.23) µmol/L], BUN[(11.60 ± 0.39) mmol/L and (8.20 ± 0.37) mmol/L], TG[(3.32 ± 0.22)mmol/L and (2.43 ± 0.25) mmol/L], TC [(2.95 ± 0.21) mmol/L and (2.24 ± 0.17) mmol/L], LDL-C [(2.03 ± 0.22) mmol/L and (1.49 ± 0.13) mmol/L], 24 h UP[(46.67 ± 2.50) mg/24 h and (25.57 ± 2.82) mg/24 h] and KI [(9.76 ± 0.30)×10³ and (8.44 ± 0.26)×10³] were significantly increased than the indexes of group NC [(6.56 ± 0.41) mmol/L, (12.63 ± 1.41) mU/L, (22.88 ± 2.36) µmol/L, (5.45 ± 0.51) mmol/L, (1.64 ± 0.11) mmol/L, (1.33 ± 0.17) mmol/L, (0.46 ± 0.05) mmol/L, (12.38 ± 1.19)/24 h and (6.78 ± 0.12)×10³]. Moreover, the above indexes in group QUE were obviously lower than group DM. There was evidence of pathological changes associated with diabetes, such as focal and segmental sclerosis and thickened basement and mesangial expansion. The expressions of ubiquitin and NF-κB p65 in renal tissues of group DM increased significantly (P < 0.01). The expression of ubiquitin and NF-κB p65 were positively related with the level of 24 h UP (r = 0.893, 0.879, P < 0.01). Compared with group DM, all above indexes in group QUE were markedly alleviated (P < 0.01). The expression of ubiquitin and NF-κB p65 was reduced but didn't reach level in group NC (P < 0.01). The increased expression of NF-κB induced by ubiquitin-proteasome system may participate in the pathogenesis of proteinuria in diabetic nephropathy. Quercetin has renal protective effects partly through reducing NF-κB p65 expression.