Esophageal squamous cell carcinoma (ESCC) is the 6th deadliest cancers worldwide. Although it is more prevalent in eastern world, it accounts for 90% of esophageal cancer worldwide. Late stage diagnosis and resistance to therapy has resulted in a poor 5-year survival rate of 20%. Alcohol consumption is a major environmental risk factor for developing ESCC. Acetaldehyde, a by-product of alcohol metabolism is a potent human carcinogen. Furthermore, single nucleotide polymorphisms (SNPs) in the alcohol metabolizing enzyme Aldehyde dehydrogenase (ALDH)-2 is strongly associated with ESCC. However, there is very limited understanding underlying the interaction between alcohol and the esophageal epithelium. Here, we utilize in vitro, ex vivo and in vivo models to study alcohol-mediated cellular injury and cytoprotective mechanisms in esophageal keratinocytes. Here we utilize RNA-Seq to identify dramatic decrease in genes and pathways associated with DNA repair and Mitochondria in alcohol exposed human esophageal keratinocytes. Alcohol caused significant structural damage to mitochondria which translated into decreased mitochondrial functional output leading to a combination of metabolic and oxidative stress. Autophagy maintained cell viability and mitochondrial homeostasis under alcohol induced stress. Autophagy induction was accompanied by a simultaneous activation of AMPK and inhibition of mTORC1. Loss of ALDH2 increased the susceptibility of esophageal keratinocytes to alcohol and acetaldehyde mediated toxicity and cell death. Cells were more reliant on autophagy in the absence of ALDH2 to negate alcohol-induced oxidative stress and DNA damage. In summary, the current work offers insight into alcohol-induced metabolic and oxidative stress in esophageal keratinocytes as the potential source of cellular injury. Finally, autophagy could be a key cytoprotective pathway in modulating response to alcohol-induced stress.