Reactive oxygen species production has recently been established as an essential contributor in the development of diabetic nephropathy (DN). Resveratrol, a natural anti-oxidants with biological activity, is known to be an activator of sirtuin1 (Sirt1). Forkhead transcription factor O1 (FoxO1) plays a role not only in regulating metabolism but also in oxidant stress. The present study was carried out to examine whether resveratrol had protective effect on diabetic kidney by modulation of the Sirt1/FoxO1 pathway. To investigate the effect of FoxO1 on oxidant stress, male Sprague-Dawley rats were injected with a single dose of 60 mg/kg streptozotocin (STZ) to induce diabetes. Here we show that the FoxO1 activity was significantly reduced and with a concomitant decrease in the expression of FoxO1 target gene, catalase in diabetic kidney. The FoxO1 downregulation correlated with an increase in the generation of malondialdehyde (MDA), a decrease in the activity of SOD and an increase in the expression of collagen IV and fibronectin proteins in renal cortex of diabetic rats. Treatment with the sirtuin agonist resveratrol, with an increase in the expression of Sirt1, significantly increased FoxO1 activity in diabetic kidney. This correlated with a decrease in the generation of MDA, an increase in the activity of SOD, a partial reversal of collagen IV and fibronectin proteins levels and more improved kidney pathological and biochemical indicators changes. Together these results indicate that it is characterized by decreased activity of FoxO1 in diabetic kidney. These data also suggest that modulation of the Sirt1/FoxO1 pathway may be a potentially useful therapeutic target for DN.