High-altitude pulmonary edema (HAPE) is a serious high-altitude illness; Dexamethasone (DEX) is widely used, but its use is limited by adverse effects including gastrointestinal and metabolic disorders. Honeysuckle (Lonicera caerulea L.) is an emerging cold-region berry; its polyphenols (LCP) show anti-hypoxic, anti-fatigue, antioxidant, hepatoprotective, and nephroprotective effects. LCP enhanced hypoxic mouse pulmonary microvascular endothelial cells (PMVECs) viability by 36.55% (P < 0.01). In a hypobaric hypoxia-induced mouse HAPE model, LCP extended survival time by 4.38 min (P < 0.01) and improved pulmonary capillary integrity, shown by reduced alveolar exudation and lung water accumulation. LCP showed no apparent toxicity and oral bioavailability. Integrated mechanistic approaches (metabolomics, network pharmacology, molecular docking, ELISA, qRT-PCR, Western blotting) demonstrated significant downregulation of EGFR and Akt (P < 0.01). Collectively, LCP mitigates HAPE by suppressing oxidative stress and maintaining NO homeostasis via coordinated iNOS/eNOS regulation through the EGFR/PI3K/Akt pathway.