The present study sought to investigate the effects of ursolic acid (UA) on the development of glomerular hypertrophy and type IV collagen accumulation, two early lesions associated with diabetic nephropathy (DN). By treating streptozotocin (STZ)-induced diabetic mice with low-dose UA (0.01% in food) for three months, the diabetes-induced glomerular hypertrophy and type IV collagen accumulation in the kidneys were found to be markedly ameliorated. Further studies identified that UA treatment suppressed diabetes-induced activations of STAT-3, ERK1/2 and JNK pathways, but not the diabetes-induced activation of the p38 pathway. Furthermore, diabetes-induced overexpression of iNOS in the renal cortex was also significantly suppressed by the treatment. UA may thus be considered as a potential therapeutic agent in treating DN.