Consumption of sugar-sweetened beverages (SSBs) have been linked to metabolic dysfunction, obesity, diabetes and enhanced risk of cardiovascular diseases across all age-groups globally. Decades of work that have provided insights into pathophysiological manifestations of sucrose overfeeding have employed paradigms that rarely mimic human consumption of SSBs. Thus, our understanding of multiorgan cross-talk and molecular and/or cellular mechanisms, which operate across scales and drive physiological derangement is still poor. By employing a paradigm of sucrose water feeding in mice that closely resembles chronic SSB consumption in humans (10% sucrose in water), we have unraveled hitherto unknown tissue-specific mechanistic underpinnings, which contribute towards perturbed physiology. Our findings illustrate that systemic impaired glucose homeostasis, mediated by hepatic gluconeogenesis and insulin resistance, does not involve altered gene expression programs in the liver. We have discovered the pivotal role of the small intestine, which in conjunction with liver and muscles, drives dyshomeostasis. Importantly, we have uncovered rewiring of molecular mechanisms in the proximal intestine that is either causal or consequential to systemic ill-effects of chronic sucrose water consumption including dysfunction of liver and muscle mitochondria. Tissue-specific molecular signatures, which we have unveiled as the primary outcome, clearly indicate that inefficient utilization of glucose is exacerbated by enhanced uptake by the gut. Besides providing systems-wide mechanistic insights, we propose that consumption of SSBs causes intestinal 'molecular addiction' for deregulated absorption of hexose-sugars, and drives diseases such as diabetes and obesity.