Objective To investigate the effects of hypoxia / reoxygenation (H/ R) on hippocampal neurons and endoplasmic reticulum (ER) stress in mice. Methods HT22 hippocampal neurons were used for subsequent experiments after H/ R treatment. The effects of H/ R on the proliferation and migration of HT22 hippocampal neurons were detected by Cell Counting Kit-8 and scratch assays and its effects on the morphology of the ER was observed by transmission electron microscopy. The effect of H/ R on the development of HT22 hippocampal neurons was observed by immunofluorescence, and its effects on ER stress in hippocampal neurons were detected by Western blot and quantitative reverse transcription-polymerase chain reaction. Results Compared with the Con group, H/ R inhibited the proliferation and migration of HT22 hippocampal neurons and decreased the expression of the neurodevelopmental protein brain-derived neurotropic factor(P<0. 05). H/ R also reduced the expression of the synaptic plasticity proteins postsynaptic density protein-95 and α-synuclein(P<0. 05). H/ R provoked pronounced ER swelling and up-regulated the key ER-stress markers glucose-regulated protein 94, binding immunoglobulin protein, and activating transcription factor 6, thereby intensifying ER stress(P<0. 05). Conclusions H/ R has a damaging effect on HT22 hippocampal neurons, which may be related to enhanced ER stress.