Central nervous system diseases are associated with hypoxia, which usually cause irreversible nerve damage, but the underlying mechanism is unclear and effective intervention strategies are lacking. This study was designed to explore the mechanism and treatment strategy of hypoxia-induced nerve injury.In this study, 13% O2 was used to treat mice for 0, 1, 3 7, and 14 days, Morris water maze and other animal behavior experiments were used to evaluate the neurological function of mice. TUNEL, BrdU, PCNA, DCX, and SOX2 staining were used to observe the apoptosis and proliferation of mouse neurons. RT-PCR and Iba1 staining were used to evaluate the release of inflammatory factors IL-1β, IL-6, and TNF-α and the activation of microglia.Short-term hypoxia promotes neurogenesis, while long-term hypoxia inhibits neurogenesis. The changes in hypoxia-induced neurogenesis were positively correlated with neurological functions, but negatively correlated with apoptosis. Moreover, intermittent hypoxic conditioning restored long-term hypoxia-induced neurological dysfunction by promoting neural stem cell generation and inhibiting the release of inflammatory factors IL-1β, IL-6, and TNF-α and the activation of microglia.Hypoxia promoted neurogenesis in a time-dependent manner, and intermittent hypoxic conditioning exerted a neuroprotective effect through promoting neural stem cell generation and suppressing inflammation induced by long-term hypoxia stress, which provided a novel concept to develop a treatment for hypoxia-related brain injury.© 2022 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.