Studies have shown that ursolic acid (UA) and empagliflozin (EM) exert therapeutic effects in the treatment of diabetic nephropathy (DN), but both drugs have disadvantages. This study explores the effect of combining these drugs compared to that of either monotherapy. A diabetic rat model was established by feeding a high-fat diet (HFD) with high-sugar content and administering a low dose of streptozotocin (STZ) via intraperitoneal injection. UA (50 mg/kg/day, po), EM (10 mg/kg/day, po) or both were administered for 8 weeks. The development of DN was determined by observing increases in urine protein, serum creatinine, urea nitrogen, and uric acid and abnormal changes in kidney morphology. UA and EM either alone or in combination can alleviate the increases in blood glucose, glycosylated haemoglobin, blood lipid levels, inflammatory factors (TNF-α, IL-1β, IL-6), oxidation factors (SOD, MDA, GSH, CAT, NO), renal fibrosis and pro-fibrosis factors (FN, E-cad, MMP-9, TIMP-1, SMA-α, TGF-β1, SMAD, MAPK). The treatments could also ameliorate DN by preventing the abnormal proliferation of glomerular mesangial cells under high-glucose conditions, aberrant apoptosis and excessive production of reactive oxygen species (ROS). In addition, UA reduces the increase in LDL-L, reverses abnormal bladder morphology and mitigates the increase in colony count caused by EM, and the combination treatment can overcome the disadvantages of the slow hypoglycaemic effect of UA. In short, UA combined with empagliflozin is more effective than either monotherapy in the treatment of DN and can cancel the adverse effects of each other. The protective effect of this regimen on the kidney may be related to reducing inflammation, oxidative stress and renal fibrosis.