One of the most important factors of adaptation to chronic brain hypoxia is the transcription factor (TF) HIF1. However, under conditions of acute hypoxia and reoxygenation, TF of the stress response NRF2 becomes to be important. The interaction of these proteins at the level of regulation of antioxidant protection and glucose metabolism was previously shown in hypoxia-sensitive cancers. Here, we studied the effect of severe hypobaric hypoxia (SHH) on HIF1 and NRF2-dependent processes in rat neocortex. We found the combined regulation of the glutathione-dependent antioxidant system by these proteins; this influenced the general anti-radical activity and cell redox status. In particular, inhibition of HIF1 prevented the SHH-induced oxidative shift a day after re-oxygenation, which was accompanied by an increase in the amount of total glutathione and glutathione reductase activity. Both of these effects were NRF2-dependent and indicate the activation of this transcription factor in response to SHH combined with HIF1 inhibition. The data obtained confirm the previous hypothesis on the maladaptive effect of HIF1 under conditions of acute hypoxia and reoxygenation and point to the contribution of NRF2 to the implementation of protective mechanisms in the posthypoxic period. The hypothesis of the interaction of these transcription factors in the (post) hypoxic period requires further verification and may significantly affect the understanding of the molecular pathomechanisms of brain hypoxia.