Alcohol abuse constitutes a significant health hazard, leading to various organ damage, notably the liver and brain. Shanxi aged vinegar (SAV) is one of the famous fermented and functional foods containing a variety of bioactive ingredients with beneficial effects on the human body. This study aimed to explore the potential protective effect of SAV in alleviating acute alcohol intoxication (AAI) in mice. It was found that SAV at 2.5 mL/kg BW effectively ameliorated the decline in behavioral abilities following alcohol consumption, characterized by a shortened sobering period. SAV reduces alcohol-induced liver damage by inhibiting hepatic function enzymes and oxidative stress levels. Additionally, SAV mitigated the overactivation of microglia and the downregulation of neurotransmitter levels including acetylcholinesterase (AchE), 5-hydroxytryptamine (5-HT) and dopamine (DA), thereby reducing ethanol-induced brain damage. Meanwhile, SAV significantly decreased concentrations of alcohol and acetaldehyde in the blood and increased alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) activities in the liver, indicating enhancement of ethanol metabolism. Moreover, we found that some gut microbiota including Verrucomicrobiota, Akkermansia, and Enterococcus were downregulated after SAV treatment in mice with AAI. These bacteria showed a negative correlation with anti-oxidative markers (glutathione (GSH) and catalase (CAT)) and enzymes related to ethanol metabolism pathways (ADH and ALDH), and a positive correlation with hepatic function markers (alanine aminotransferase (ALT), aspartate aminotransferase (AST), and malondialdehyde (MDA)), alcohol metabolites (alcohol and acetaldehyde) and neurotransmitters (AchE, 5-HT, and DA). However, Bacteroidota, norank_f_Muribaculaceae, and Alistipes exhibited the opposite direction. These findings suggest that SAV possesses protective effects against hepatic and neuro-toxicity, and could be a potential functional food for AAI prevention.