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High-altitude (HA, >2500 m) hypobaric hypoxia, together with oxidative stress and ultraviolet radiation, can induce DNA damage and disrupt telomere homeostasis. Telomeres are essential for chromosomal integrity and cellular viability and are particularly vulnerable to oxidative damage, which may contribute to High-Altitude Pulmonary Edema (HAPE) and its severity. The association among telomere dynamics, oxidative stress, and HAPE risk, however, remains poorly understood. This case-control study included HA native residents (HLs, n = 247), HAPE-free sojourners (controls, n = 262), and HAPE patients (n = 371), with patients further classified as mild, moderate, or severe. The study investigated associations among telomere length, telomerase activity, oxidative stress, telomere-associated gene expression, single-nucleotide polymorphisms (SNPs), and protein–protein interactions. Telomere length was measured by quantitative real-time PCR (qRT-PCR), 8-hydroxy-2′-deoxyguanosine (8-oxo-dG) by ELISA, telomerase activity using the TRAPeze assay, gene expression by qRT-PCR, and SNPs using the Global Screening Array (GSA). Protein–protein interactions were analyzed using STRING. HAPE patients exhibited shorter telomeres, increased telomerase activity, and elevated 8-oxo-dG levels (P < 0.0001). In HAPE patients, telomere length was positively correlated with telomerase activity and negatively correlated with 8-oxo-dG levels (P < 0.01), while telomerase activity was positively correlated with 8-oxo-dG. Differential gene expression and seven significant SNPs (P ≤ 0.05) were also identified. These findings suggest that oxidative stress-associated telomere attrition and altered telomerase activity may contribute to HAPE susceptibility and severity.