High-altitude exposure, characterized by hypobaric hypoxia, cold, and intense radiation, profoundly remodels the gut microbiota, triggering a cascade of physiological and pathological changes that extend far beyond the gastrointestinal tract. As millions travel to or reside in regions above 2500 meters, understanding this gut-centric axis has become critical for managing health risks. Hypoxia disrupts the delicate balance of the gut ecosystem, leading to dysbiosis, impaired barrier function, and increased intestinal permeability. This allows bacterial translocation and systemic inflammation, which underpin conditions like acute and chronic mountain sickness. Crucially, the gut microbiome acts as a dynamic environmental sensor; its altered production of metabolites—particularly short-chain fatty acids (SCFAs) and bile acids—directly influences host energy metabolism, immune responses, and acclimatization capacity. These changes are increasingly implicated in a spectrum of diseases, from metabolic disorders to colorectal cancer, positioning the gut as a central mediator of high-altitude health. This review synthesizes evidence from human and animal studies to elucidate how high-altitude stress reshapes the microbial landscape, explores the mechanisms linking microbiota to disease, and evaluates emerging microbiome-based interventions for promoting resilience.