Adaptation to high-altitude hypoxia is characterized by systemic and organ-specific metabolic changes. This study investigates whether intestinal metabolic rewiring is a contributing factor to hypoxia adaptation. We conducted a longitudinal analysis over 108 days, with seven time points, examining fecal metabolomic data from a cohort of 46 healthy male adults traveling from Chongqing (a.s.l. 243 m) to Lhasa (a.s.l. 3,658 m) and back. Our findings reveal that short-term hypoxia exposure significantly alters intestinal metabolic pathways, particularly those involving purines, pyrimidines, and amino acids. A notable observation was the significantly reduced level of intestinal uric acid, the end product of purine metabolism, during acclimatization (also called acclimation) and additional two long-term exposed cohorts (Han Chinese and Tibetans) residing in Shigatse, Xizang (a.s.l. 4,700 m), suggesting that low intestinal uric acid levels facilitate adaptation to high-altitude hypoxia. Integrative analyses with gut metagenomic data showed consistent trends in intestinal uric acid levels and the abundance of key uric acid-degrading bacteria, predominantly from the Lachnospiraceae family. The sustained high abundance of these bacteria in the long-term resident cohorts underscores their essential role in maintaining low intestinal uric acid levels. Collectively, these findings suggest that the rewiring of intestinal uric acid metabolism, potentially orchestrated by gut bacteria, is crucial for enhancing human resilience and adaptability in extreme environments.