We observe that Natural Killer (NK) cells, which can kill target tumour cells, infiltrate hypoxic tumour areas. Cellular adaptation to low oxygen is mediated by Hypoxia-inducible transcription factors (HIFs) that play a pivotal role in driving immune responses and angiogenesis. We show that deletion of HIF-1α in NK cells impairs tumour cell killing in vitro. Paradoxically, in vivo, NK cell HIF-1α-deficiency inhibits tumour growth despite impaired immune surveillance. Tumours developing in these conditions were characterized by a high density network of immature vessels devoid of pericytes, severe hemorrhage and increased hypoxia, indicating non-functional angiogenesis. Mechanistically, loss of HIF-1α in NK cells reduced expression of antiangiogenic factors within the tumour. Hence, in contrast to other cell types, in NK cells the hypoxic response acts as an inhibitor of angiogenesis, yet, this promotes tumour growth by allowing the formation of functionally improved vessels. Furthermore, HIF-1α-deficiency in NK cells accelerates physiological angiogenesis and non-fibrotic wound healing but compromises the antimicrobial defense. As a consequence, mice with a deletion of HIF-1α in NK cells show increased susceptibility to sepsis during bacterial skin infections. In summary, we demonstrate that the hypoxic response in NK cells controls tumor immune surveillance, vascular remodeling and antimicrobial defense mechanisms.