Exposure of marine life to low oxygen is accelerating worldwide via climate change and localized pollution. Mass coral bleaching and mortality have recently occurred where reefs have experienced chronic low oxygen events. However, the mechanistic basis of tolerance to oxygen levels inadequate to sustain normal functioning (i.e. hypoxia) and whether it contributes to bleaching susceptibility, remain unknown. We therefore experimentally exposed colonies of the environmentally resilient Acropora tenuis, a common reef-building coral from the Great Barrier Reef, to deoxygenation–reoxygenation stress that was aligned to their natural night–day light cycle. Specifically, the treatment involved removing the ‘night-time O2 buffer’ to challenge the inherent hypoxia thresholds. RNA-Seq analysis revealed that coral possess a complete and active hypoxia-inducible factor (HIF)-mediated hypoxia response system (HRS) homologous to other metazoans. As expected, A. tenuis exhibited bleaching resistance and showed a strong inducibility of HIF target genes in response to deoxygenation stress. We applied this same approach in parallel to a colony of Acropora selago, known to be environmnetally susceptible, which conversely exhibited a bleaching phenotype response. This phenotypic divergence of A. selago was accompanied by contrasting gene expression profiles indicative of varied effectiveness of their HIF-HRS. Based on our RNA-Seq analysis, we propose (a) that the HIF-HRS is central for corals to manage deoxygenation stress and (b) that key genes of this system (and the wider gene network) may contribute to variation in coral bleaching susceptibility. Our analysis suggests that heat shock protein (hsp) 70 and 90 are important for low oxygen stress tolerance and further highlights how hsp90 expression might also affect the inducibility of coral HIF-HRS in overcoming a metabolic crisis under deoxygenation stress. We propose that differences in coral HIF-HRS could be central in regulating sensitivity to other climate change stressors—notably thermal stress—that commonly drive bleaching.