To better understand human adaptation to stress, and in particular to hypoxia, we took advantage of one of nature’s experiments at high altitude (HA) and studied Ethiopians, a population that is well-adapted to HA hypoxic stress. Using whole-genome sequencing, we discovered that EDNRB (Endothelin receptor type B) is a candidate gene involved in HA adaptation. To test whether EDNRB plays a critical role in hypoxia tolerance and adaptation, we generated EdnrB knockout mice and found that when EdnrB^−/+ heterozygote mice are treated with lower levels of oxygen (O₂), they tolerate various levels of hypoxia (even extreme hypoxia, e.g., 5% O₂) very well. For example, they maintain ejection fraction, cardiac contractility, and cardiac output in severe hypoxia. Furthermore, O₂ delivery to vital organs was significantly higher and blood lactate was lower in EdnrB^−/+ compared with wild type in hypoxia. Tissue hypoxia in brain, heart, and kidney was lower in EdnrB^−/+ mice as well. These data demonstrate that a lower level of EDNRB significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Transcriptomic profiling of left ventricles revealed three specific genes [natriuretic peptide type A (Nppa), sarcolipin (Sln), and myosin light polypeptide 4 (Myl4)] that were oppositely expressed (q < 0.05) between EdnrB^−/+ and wild type. Functions related to these gene networks were consistent with a better cardiac contractility and performance. We conclude that EDNRB plays a key role in hypoxia tolerance and that a lower level of EDNRB contributes, at least in part, to HA adaptation in humans.