Sirtuin1 (SIRT1), a class III histone deacetylase, exerts a protective role against kidney injury. However, its functions in renal ischemia/reperfusion (I/R) injury remains unclear as yet. In this study, we established acute kidney injury (AKI) rat model through renal ischemia and reperfusion, and the role of SIRT1 in I/R-induced AKI was investigated both in vivo and in vitro. In in vivo study, SIRT1 was expressed in tubular epithelial cells (TECs) and its expression was upregulated after I/R treatment. Meanwhile, our in vitro experiment confirmed that the expression of SIRT1 was also elevated in human renal proximal tubular epithelial (HK2) cells treated with hypoxia and reoxygenation (H/R). Notably, activation of SIRT1 by resveratrol (Res, an activator of SIRT1) could significantly ameliorate renal function and reduce the TECs apoptosis in rats. Likewise, Res intervention also reduced the apoptosis and the production of reactive oxygen species in HK2 cells. Furthermore, we found that the autophagy level was upregulated in I/R injury, which could be raised further through resveratrol intervention; and chloroquine (CQ, an autophagy inhibitor) did reverse these protective effects of SIRT1 activation. Taken together, our results suggest that SIRT1 plays a protective role by autophagy induction in I/R- induced AKI. Its role might serve as a preventive approach in I/R-associated AKI.