Following prolonged exposure to hypoxic conditions, for example, due to ascent to high altitude, aging or stroke, cognitive deficits can develop. The exact nature and genesis of hypoxia-induced cognitive deficits remain unresolved. Curcumin has been reported to stimulate neurogenesis and reduce neuronal degeneration. This study aimed to investigate the effect of curcumin on cognitive deficits in hypoxic-brain injury mice and its potential mechanism. Eight-week-old male C57BL/6J mice were exposure to normobaric-hypoxia (13%O) 14 days to establish hypoxic-brain injury models. Morris water maze and novel object recognition were used to detect the cognitive function of each mouse. Immunofluorescence assays, including Fluoro-Jade C (FJC) and bromodeoxyuridine (BrdU), were used to detect neuronal degeneration and neurogenesis. Thy1-YFP transgenic mice were used to detect synapse plasticity. Our results showed that curcumin administration rescued the impaired cognition of mice, shown as enhanced BrdU and dendritic spine in hippocampus. At the molecular level, curcumin was found to promote the expression of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95). The results of primary hippocampal neuron detection showed that curcumin could promote dendritic growth. In conclusion, our study indicates that curcumin, increased BDNF and PSD95 expression and contacted with interneurons, salvaged of interneurons may normalize ambient neuroplasticity, resulting in the preservation of neurogenesis processes as well as contributing to improve cognitive performance.