Alcoholic fatty liver (AFL) is susceptible to ischemia/reperfusion (I/R) injury, responding with inflammation and extensive hepatocellular damage. Autophagy maintains cellular homeostasis and regulates inflammation and lipid metabolism. 2-Methoxyestradiol (2-ME2), an endogenous metabolite of estradiol, exhibits antioxidant and anti-inflammatory properties. This study examined the cytoprotective mechanisms of 2-ME2 on hepatic I/R in AFL, focusing on autophagy signaling. C57BL/6 mice were fed an ethanol diet (ED) to induce AFL, or a control diet (CD) for 6 weeks, and then subjected to 60 min of ischemia and 5 h of reperfusion. 2-ME2 (15 mg/kg, i.p.) was administered 12 h before ischemia and 10 min before reperfusion, and sirtinol (sirtuin 1 (SIRT1) inhibitor, 10 mg/kg, i.p.) was administered 30 min before reperfusion. After reperfusion, ED animals showed higher serum aminotransferase activities and proinflammatory cytokine levels, and more severe histological changes compared with CD animals. These alterations were attenuated by 2-ME2. In the ED I/R group, autophagy and mitophagy were significantly impaired, as indicated by decreased hepatic levels of microtubule-associated protein 1 light chain 3 II and parkin protein expression, and increased p62 protein expression, which were attenuated by 2-ME2. The hepatic levels of Atg12–5 complex, Atg3, Atg7, lysosomal-associated membrane protein 2 and Rab7 protein expression significantly decreased in ED I/R animals, which were attenuated by 2-ME2. In the ED I/R group, the level of SIRT1 protein expression and its catalytic activity significantly decreased, which were attenuated by 2-ME2. Sirtinol reversed the stimulatory effect of 2-ME2 on autophagy. Our findings suggest that 2-ME2 ameliorates I/R-induced hepatocellular damage in AFL through activating SIRT1-mediated autophagy signaling.