Chronic alcohol consumption induces oxidative stress not only in the liver but also in the gastrointestinal tract, where prolonged intestinal ethanol absorption plays a pivotal and underrecognized role. This review reframes ethanol pharmacokinetics to emphasize sustained jejunal and ileal uptake, which maintains elevated blood alcohol levels and perpetuates redox imbalance across the gut-liver axis. We integrate recent findings on ethanol-induced barrier dysfunction, CYP2E1-mediated ROS production, microbial dysbiosis, and mitochondrial disruption, proposing that the intestine is an active site of injury and a driver of systemic inflammation. Key mechanistic insights reveal that gut-derived endotoxins, compromised epithelial integrity, and microbiome-mitochondria interactions converge to exacerbate hepatic and extrahepatic damage. We further explore emerging therapeutic strategies-ranging from NAD⁺ repletion and probiotics to fecal microbiota transplantation-that target this upstream pathology. Recognizing prolonged intestinal ethanol absorption as a clinically meaningful phase offers new directions for early intervention and redox-based treatment in alcohol-associated disease. A less commonly emphasized feature of ethanol pharmacokinetics is its prolonged absorption within the small intestine, particularly under conditions of delayed gastric emptying [ 3 ]. This mechanism prolongs systemic exposure beyond the initial drinking episode and may play a critical role in shaping redox homeostasis. Although the term “intestinal drinking” has been proposed to describe this sustained intestinal phase, we use it here primarily as a conceptual tool to contextualize a range of recent findings [ 4 , 5 ]. Indeed, this phase of prolonged intestinal ethanol absorption has implications for alcohol clearance kinetics, tissue-specific oxidative damage, and ethanol–drug interactions. In particular, therapies that target intestinal redox signaling and epithelial–microbial crosstalk may interrupt the gut–liver injury loop before hepatic dysfunction ensues. This review aims to bridge gaps among recent findings in ethanol pharmacokinetics, redox biology, and gut–liver axis research. By synthesizing these insights, we outline a framework in which sustained and prolonged intestinal ethanol absorption functions as a critical driver of redox imbalance and systemic inflammation in alcohol-associated disease ( Figure 1 ). This systems-level approach may yield novel targets for early intervention and enhance our mechanistic understanding of gut-centered pathogenesis in alcohol use disorders. Figure 1 Schematic diagram showing the proposed model depicting effect of defecation on hangover the day after binge ethanol drinking. Ethanol absorption from the large intestine ceases after defecation, thereby halting acetaldehyde production and enabling the degradation of hangover-related compounds, such as acetaldehyde, methanol, and isopropanol. Abbreviations: EtOH, ethanol; MeOH, methanol; iPrOH, isopropanol; Acetalde, acetaldehyde; Formalde, formaldehyde; ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase. 2. These changes are especially important in understanding systemic toxicity, as ethanol’s absorption kinetics influence downstream tissue exposure and metabolic overload. In both animal models and human studies, delayed gastric emptying—induced by high-fat meals, opioid medications, or diabetes—prolongs the transit time of ethanol into the small intestine. In these contexts, ethanol continues to be absorbed over several hours, maintaining elevated BAC levels despite cessation of drinking [ 25 , 26 ]. This extended exposure phase corresponds to sustained oxidative activity in both intestinal and hepatic tissues, contributing to systemic redox imbalance [ 27 ]. Although the term “intestinal drinking” remains conceptual, it reflects a reproducible physiological pattern with implications for alcohol pharmacokinetics and toxicity. Recognizing this phase expands our understanding of ethanol’s systemic effects, particularly in vulnerable populations, such as individuals with metabolic syndrome, alcohol use disorder, or chronic gastrointestinal conditions [ 32 , 33 ]. Prolonged intestinal retention also raises concern for synergistic toxicity with substances that share metabolic pathways. The oxidative burden is thus not only local but systemic, establishing the gut as a persistent contributor to alcohol-related multi-organ injury. By characterizing ethanol pharmacokinetics beyond the stomach, we highlight a critical but underappreciated determinant of redox balance and tissue injury. This section lays the foundation for understanding how sustained ethanol absorption from the intestine propagates oxidative stress along the gut–liver axis, requiring an integrative metabolic and immunologic response framework. 3. Prolonged Intestinal Ethanol Absorption and Redox Imbalance Prolonged exposure to ethanol within the small intestine leads to a distinct set of localized injuries, primarily driven by redox imbalance. The metabolic activity of enterocytes plays a key role in this context, especially given their capacity to express ethanol-metabolizing enzymes, such as CYP2E1. Unlike hepatic cells, intestinal epithelial cells are in direct contact with luminal ethanol and microbial products, making them uniquely vulnerable to oxidative insults [ 41 , 42 ]. Sustained intestinal ethanol absorption thus represents a pathophysiological amplifier that intensifies alcohol-related disease severity and therapeutic resistance. 4. Gut–Liver Axis and Redox Amplification Once microbial byproducts and inflammatory signals breach the intestinal barrier, they are rapidly conveyed to the liver via the portal vein. This anatomical arrangement places the liver in direct and continuous contact with gut-derived insults, particularly lipopolysaccharide (LPS), peptidoglycans, and bacterial DNA.