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