In this study, we employed an integrated proteomic and metabolomic approach to systematically analyze the proteome and metabolome profiles of SHRs following prolonged exposure to a high-altitude hypoxic environment. Bioinformatics and enrichment analysis revealed that proteins with significant differential expression were predominantly involved in pathways such as oxidative phosphorylation, thermogenesis, TCA cycle, and carbon metabolism. Further analysis indicated that alterations in key metabolites, including thiamine, S-adenosylhomocysteine, pantothenic acid, fumaric acid, and homoserine, interact with differentially expressed proteins, collectively contributing to the modulation of blood pressure regulation in SHRs under hypoxic conditions. This research provides new molecular insights into understanding the impact of high-altitude hypoxia on the blood pressure regulatory mechanisms in spontaneously hypertensive rats.