Elephant seals experience extreme hypoxemia during diving bouts. Similar depletions in oxygen availability characterize pathologies including myocardial infarction and ischemic stroke in humans, but seals manage these repeated episodes without injury. However, the real-time assessment of the molecular changes underlying protection against hypoxic injury in seals remains restricted by their at-sea inaccessibility. Hence, we developed a proliferative arterial endothelial cell culture system to assess the molecular response to prolonged hypoxia. Seal and human cells exposed to 1% O 2 for up to 6 h demonstrated differential responses to both acute and prolonged hypoxia. Seal cells decouple stabilization of the hypoxia-sensitive transcriptional regulator HIF-1α from angiogenic signaling at both the transcriptional and cellular level. Rapid upregulation of genes involved in the glutathione (GSH) metabolism pathway supported maintenance of GSH pools and increases in intracellular succinate in seal but not human cells during hypoxia exposure. High maximal and spare respiratory capacity in seal cells after hypoxia exposure occurred in concert with increasing mitochondrial branch length and independent from major changes in extracellular acidification rate, suggesting seal cells recover oxidative metabolism without significant glycolytic dependency after hypoxia exposure. In sum, our studies show that in contrast to human cells, seal cells adapt to hypoxia exposure by dampening angiogenic signaling, increasing antioxidant protection, and maintaining mitochondrial morphological integrity and function.