Objective To study the protective effect of safflower yellow (SY) in mice with diabetic nephropathy (DN) induced by streptozotocin (STZ). Methods DN was induced by the intraperitoneal injection of STZ (50 mg / kg) for 5 consecutive days. Thirty-six male C57 BL/ 6J mice with DN were randomly allocated to a model group, and SY-10 mg / kg, SY-30 mg / kg, and SY-90 mg / kg groups. The three experimental groups were administered SY once daily for 10 weeks. Their blood glucose and body mass were monitored, and blood urea nitrogen ( BUN) and serum creatinine ( Scr) were analyzed. Renal pathology was assessed using hematoxylin and eosin-stained sections. The protein expression levels of PKC, P-Raf, Raf, P-ERK, ERK were measured using Western blot analysis. The contents of GSH, MDA, and SOD, and the expression levels of TNF-α, IL-6, and IL-1β were measured using ELISA kits. Results Compared with a control group, the food and water consumption and blood glucose concentration were higher, and the body mass was lower in the model group. The body mass, blood glucose, BUN, and Scr were higher in all the treatment groups, but the glomerular hypertrophy, basement membrane thickening, and vacuolar degeneration of renal tubules were ameliorated. The contents of SOD and GSH were higher, whereas that of MDA was lower, and the expression levels of proinflammatory factors were lower in the treatment groups. Finally, the protein expression of PKC, P-Raf, and P-ERK was lower in the SY-30 and SY-90 groups. Conclusions SY may ameliorate inflammation and oxidative stress in DN, which might be mediated via the PKC/ Ras-Raf-MEK-ERK signaling pathway.