Diabetic nephropathy (DN) is a common cause of chronic kidney disease and end-stage renal disease, which can be triggered by oxidative stress. In this study, we investigated the renoprotective effect of the ethyl acetate extract of Salvia miltiorrhiza (EASM) on DN and examined the underlying molecular mechanism. We observed that EASM treatment attenuated metabolic abnormalities associated with hyperglycemic conditions in the experimental DN model. In streptozotocin (STZ)-induced mice, EASM treatment reduced albuminuria, improved renal function and alleviated the pathological alterations within the glomerulus. To mimic the hyperglycemic conditions in DN patients, we used high glucose (25[Formula: see text]mmol/L) media to stimulate mouse mesangial cells (MMCs), and EASM inhibited high glucose-induced reactive oxygen species. We also observed that EASM enhanced the expression of nuclear factor erythroid-2-related factor 2 (Nrf2), which mediated the anti-oxidant response, and its downstream gene heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1) with concomitant decrease of expression of kelch-like ECH-associated protein 1 (keap1) both in vitro and in vivo. Taken together, these results suggest that EASM alleviates the progression of DN and this might be associated with activation of Nrf2.