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At high altitudes, oxygen deprivation can cause pathophysiological changes. Liver tissue function is known to impact whole-body energy metabolism; however, how these functions are affected by chronic hypoxia remains unclear. We aimed to elucidate changing characteristics underlying the effect of chronic hypoxia on protein and amino acid metabolism in mouse livers. Mice were maintained in a hypobaric chamber simulating high altitude for 4 weeks. Livers were collected for metabolomic analysis via ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. For transcriptomics analysis, we conducted RNA sequencing of hepatic tissues followed by Gene Ontology and KEGG pathway enrichment analyses. Chronic hypoxic exposure caused metabolic disorders of amino acids and their derivatives in liver tissue. We identified a number of metabolites with significantly altered profiles (including amino acids, peptides, and analogues), of which serine, phenylalanine, leucine, proline, aspartic acid, L-glutamate, creatine, 5-aminovaleric acid, L-hydroxyarginin, and g-guanidinobutyrate showed great potential as biomarkers of chronic hypoxia. A total of 2124 genes with significantly different expression levels were identified in hypoxic liver tissue, of which 1244 were upregulated and 880 were downregulated. We found pathways for protein digestion and absorption, arginine and proline metabolism, and mineral absorption related to amino acid metabolism were affected by hypoxia. Our findings surrounding the regulation of key metabolites and differentially expressed genes provide new insights into changes in protein and amino acid metabolism in the liver that result from chronic hypoxia.