In this study, we report for the first time that (i) chronic alcohol consumption reduces hepatic TRPC3 expression without affecting other TRPCs; (ii) miR-339-5p contributes to TRPC3 reduction in response to alcohol-induced oxidative stress; (iii) TRPC3 loss aggravates alcohol-induced hepatic damage, steatosis, and mitochondrial subunit abundance; (iv) restoring hepatic TRPC3 arrests the pathological progression of alcohol-induced liver disease; and (v) CaMKK2/AMPK suppression contributes to TRPC3 loss-mediated hepatocyte injury and dysregulated lipid metabolism. This evidence concerns the gene TRPC3 and liver disorder.