Omentin-1, a novel identified adipokine, always significantly decreases in patients with metabolic syndrome. However, the functional roles of omentin-1 in diabetic nephropathy (DN) remains largely unknown. In the present study, we found that omentin-1 treatment could improve renal function of type 2 diabetic db/db mice. ELISA assay and immunohistochemistry staining showed that omentin-1 reduced the productions of proin-flammatory cytokines (IFN-gamma, TNF-alpha, MCP-1 and IL-8), and improved oxidative stress level (CAT, MDA and SOD) in the kidney tissue, indicating omentin-1 could relieved the inflammatory response and suppressed oxidative stress. Mechanistic analysis demonstrated that omentin-1 down-regulated miR-27a expression, and subsequently inhibited oxidative stress and inflammation. Luciferase reporter assay and western blot further revealed that miR-27a directly targeted the 3' untranslated region (UTR) of nuclear factor erythroid 2-like 2 (Nrf2) and reduced its expression in type 2 DN. Taken together, these findings provide a new function of omentin-1 in renal protection and also delineate multiple potential targets for therapeutic intervention for type 2 DN.