Abstract: Individuals who reside at high altitudes for extended periods or those who visit these regions briefly frequently experience high-altitude response, which triggers a series of physiological and pathological changes in the body, ultimately causing altitude sickness. One of the most critical features of high-altitude environments is hypoxia. Recent studies have demonstrated that hypoxia-inducible factor 1 (HIF-1) plays a central role in mediating the body’s response to hypoxic conditions at high altitudes. HIF-1, a heterodimeric transcription factor composed of an oxygen-sensitive subunit α (HIF-1α) and a constitutively expressed subunit β (HIF-1β), directly regulates the expression of multiple target genes, thereby modulating various physiological processes essential for cellular adaptation to hypoxia. According to a substantial body of research, aberrant expression of HIF-1 is implicated in the pathogenesis and progression of various diseases, including altitude sickness, cardiovascular disorders, neurological conditions, inflammatory diseases, cognitive impairment, immune dysregulation, and cancer. In this review, we provided an in-depth examination of the structural characteristics and regulatory mechanisms governing HIF-1 expression, discussed its downstream target genes, and highlighted the inhibitors currently under development. Additionally, we summarized the pivotal role and underlying mechanisms of HIF-1 in the development of altitude sickness, particularly its regulatory role in the pathophysiological processes of high-altitude pulmonary edema (HAPE), high-altitude cerebral edema (HACE), and high-altitude pulmonary hypertension (HAPH). Through a thorough examination of the role of HIF-1, we aim to provide a theoretical foundation and potential therapeutic targets for the prevention and treatment of altitude sickness.