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High altitude has a considerable impact on the pathophysiology of the human cardiovascular system and disease occurrence. We aim to use an integrated approach of metabolomics and proteomics to reveal key pathways and biomarkers of hypertension at high altitude. Thirty Tibetan patients with hypertension and 30 healthy individuals residing on the Tibetan Plateau at a very high altitude (> 4500 m) were included in the study. Metabolomic analysis was conducted using Vanquish ultra-high performance liquid chromatography, while proteomic analysis utilized the timsTOF Pro2 mass spectrometer. Correlation analysis revealed key signaling pathways and biomarkers associated with hypertension in Tibetan patients. The results showed 87 differentially expressed metabolites and 61 differentially expressed proteins in individuals with hypertension at high altitude. The results of metabolomic differential metabolite pathway analysis indicated that Caffeine metabolism had the most significant impact. Specific metabolites like PI(16:0/16:0), Caffeine, and Plastoquinone 3 were found to be significantly up-regulated in hypertensive patients. The combination of five metabolites achieved an area under the curve (AUC) of 0.871 for hypertension prediction. Proteomic analysis revealed that the identified differential proteins primarily functioned in signaling receptor binding. It was confirmed that Creatine kinase B (CKB) and Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) could serve as a protein biomarker combination for hypertension in plateau regions, showing an AUC of 0.764 (0.585-0.944). Upon conducting an integrated analysis of metabolomics and proteomics, the combined AUC improved to 0.982 (0.949-1.000). A comprehensive analysis utilizing metabolomics and proteomics revealed that alterations in signal transduction-related pathways and lipid metabolism pathways were implicated in hypertension among plateau populations. Additionally, YWHAZ was observed as a potential biomarker for this condition.