Hypoxia is a common feature of solid tumors, playing a pivotal role in remodeling tumor immune microenvironment through hypoxia inducible factors (HIF). Although the inhibitory role of HIF1α in NK cells has been reported, whether and how HIF2α regulates NK cells remain unclear. In this study, we found that both mouse and human tumor-infiltrating NK cells up-regulate Epas1 expression. Conditional deletion of Epas1 in NK cells resulted in reduced tumor growth and enhanced NK cell antitumor activities. Under hypoxia conditions, NK cells had defects in cell survival and cytotoxic functions, while Epas1 knockout mitigated hypoxia-induced NK cell defects. In contrast, the killing ability and proliferation rate of human NK92 cells overexpressing HIF2A was impaired. Therefore, these findings reveal a critical role of HIF2α in hypoxia-induced NK cell defect and highlight HIF2α as a promising target for NK cell-based cancer immunotherapies.