Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid) is purified from rhubarb (Rheum officinale), a widely used traditional Chinese herb. In our previous studies, rhein was shown to be effective in ameliorating diabetic renal pathological changes and attenuating hyperlipidemia. Statins have also been proven to ameliorate renal pathological changes associated with diabetic nephropathy (DN) through lipid-dependent and -independent mechanisms. We here study the protective and regulatory effects of rhein on renal injury and dyslipidemia in db/db mice with DN, using simvastatin as the control, and provide information on the mechanisms by which rhein protects against renal damage from DN. The results indicated that urinary albumin excretion (UAE) was reduced after 8 weeks of treatment in the rhein group, and 12 weeks in the simvastatin group. The morphometric analysis revealed that levels of extracellular matrix (ECM) significantly decreased in the rhein group after the full treatment course, but not in the simvastatin group. The more powerful effects of rhein on decreasing transforming growth factor-beta1 (TGF-beta1) and fibronectin immunohistochemistry expression in renal tissue were also observed. And the plasma levels of cholesterol (Chol), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and ApoE all decreased in both the rhein and the simvastatin groups. Together, our data suggested that both rhein and simvastatin regulate dyslipidemia. The powerful effect of rhein in renal protection is due to its widespread effects. Rhein is a new drug that can decrease lipid levels and protect against DN progression in a different fashion with simvastatin.