This study investigated alterations in hematological parameters, gut microbiota composition, and fecal and plasma metabolic profiles among high-altitude residents during reoxygenation periods of 1 week, 1 month, and 4 months to elucidate the effects of reoxygenation on human physiology and metabolism. Exposure to high altitudes alters intestinal flora, plasma and fecal metabolites, disrupting their metabolic balance. Distinct differences in amino acid, lipid, energy, immune, cofactor, and vitamin metabolism pathways were detected between high- and low-altitude populations, with a partial recovery of disparities during reoxygenation. Although the gut microbiota exhibited limited adaptive homeostasis to altitude variations, the abundance of microbial taxa and the expression levels of fecal metabolites during the initial reoxygenation phase, particularly during the first week, were sensitive to the reoxygenated environment. Through 16S rRNA gene sequencing and bioinformatics analysis, operational taxonomic units (OTUs) were annotated at the genus level, revealing that the genera , along with plasma L-arginine, S1P, and alpha-D-glucose, emerged as potential biomarkers for the first week of reoxygenation among high-altitude populations. Notably, a marked change in oxidative stress levels and an increase in antioxidant capacity were observed in high-altitude residents during early reoxygenation. Tyrosine metabolism, which is jointly regulated by the plasma and fecal metabolites and gut microbiota, plays an important role under high-altitude conditions during initial reoxygenation. Additionally, the plasma metabolites pyridoxine and hypoxanthine and the genus correlated significantly with high-altitude deacclimatization syndrome scores during the first week of reoxygenation.IMPORTANCEOur research focuses on the prompt activation of tyrosine metabolism in plasma following reoxygenation, along with the regulatory mechanisms employed by the intestinal microbiota and the metabolism of feces to modulate this metabolic process. Notably, in the initial stages of reoxygenation, specific microbial genera such as , and , alongside plasma biomarkers including L-arginine, S1P, and alpha-D-glucose, emerge as pivotal players. Additionally, our findings reveal a distinct hematological profile characterized by a decrease in the MCHC and increases in the MCV and RDW-SD during the first week of reoxygenation, and this temporal window marked a crucial juncture in the plasma metabolome. Whereas the first month of reoxygenation signified a pivotal phase in the gut microbiome's adaptation to altered environmental conditions, as evidenced by alterations in alpha diversity.