At-risk alcohol use is a major contributor to the global health care burden and leads to preventable deaths and diseases including alcohol addiction, alcoholic liver disease, cardiovascular disease, diabetes, traumatic injuries, gastrointestinal diseases, cancers, and fetal alcohol syndrome. Excessive and frequent alcohol consumption has increasingly been linked to alcohol-associated tissue injury and pathophysiology, which have significant adverse effects on multiple organ systems. Extensive research in animal and in vitro models has elucidated the salient mechanisms involved in alcohol-induced tissue and organ injury. In some cases, these pathophysiological mechanisms are shared across organ systems. The major alcohol- and alcohol metabolite-mediated mechanisms include oxidative stress, inflammation and immunometabolic dysregulation, gut leak and dysbiosis, cell death, extracellular matrix remodeling, endoplasmic reticulum stress, mitochondrial dysfunction, and epigenomic modifications. These mechanisms are complex and interrelated, and determining the interplay among them will make it possible to identify how they synergistically or additively interact to cause alcohol-mediated multiorgan injury. In this article, we review the current understanding of pathophysiological mechanisms involved in alcohol-induced tissue injury.