Insulin resistance is often characterized as the most critical factor contributing to the development of type 2 diabetes. SIRT1 has been reported to be involved in the processes of glucose metabolism and insulin secretion. However, whether SIRT1 is directly involved in insulin sensitivity is still largely unknown. Here we show that SIRT1 is downregulated in insulin-resistant cells and tissues and that knockdown or inhibition of SIRT1 induces insulin resistance. Furthermore, increased expression of SIRT1 improved insulin sensitivity, especially under insulin-resistant conditions. Similarly, resveratrol, a SIRT1 activator, enhanced insulin sensitivity in vitro in a SIRT1-dependent manner and attenuated high-fat-diet-induced insulin resistance in vivo at a dose of 2.5 mg/kg/day. Further studies demonstrated that the effect of SIRT1 on insulin resistance is mediated by repressing PTP1B transcription at the chromatin level. Taken together, the finding that SIRT1 improves insulin sensitivity has implications toward resolving insulin resistance and type 2 diabetes.