Hepatic ischemia and reperfusion injury are characterized by impaired autophagy, mitochondrial dysfunction, and subsequent compromise of cellular homeostasis following hepatic surgery or transplantation. Nobiletin, a natural flavonoid, is a beneficial antioxidant that possesses anti-inflammatory and anti-cancer activities. We investigated the effect of nobiletin on hepatic IR injury and described the underlying mechanisms. C57BL/6 mice were subjected to 60 min of partial hepatic ischemia, treated with nobiletin (5 mg/kg) or vehicle at the start of reperfusion, and killed at 5 h of reperfusion. Hepatic ischemia and reperfusion increased hepatocellular oxidative damage, inflammation, and cell death, but these changes were alleviated upon nobiletin treatment. Nobiletin increased the expression of proteins that control autophagy, mitochondrial dynamics, and biogenesis. Specifically, the SIRT-1/FOXO3a and PGC-1α pathways were activated by nobiletin. IR-induced AKT activation was associated with FOXO3a phosphorylation, which resulted in a significant reduction in the nuclear FOXO3a levels and potentially attenuated autophagy-regulatory gene expression. Nobiletin increased FOXO3a expression and its nuclear translocation via the inhibition of AKT. Specific inhibition of SIRT-1 abolished the protective effect of nobiletin, causing decreased FOXO3a expression, followed by autophagy induction and decreased PGC-1α expression and mitochondrial dynamics. Taken together, our data indicate that SIRT-1 directly mediates the protective effect of nobiletin against hepatic ischemia and reperfusion injury. The activation of autophagy and mitochondrial function through the SIRT-1/FOXO3a and PGC-1α pathways indicate that nobiletin could have therapeutic potential for treating hepatic ischemia and reperfusion injury.