BACKGROUND: The neuroprotective roles of mesenchymal stem cells (MSCs) in brain injury are elicited at least partially through the secretion exosomes containing microRNAs (miRNAs). We herein investigate the protective function of bone marrow MSCs (BMSCs)-derived exosomes harboring miR-455-3p against hippocampal neuronal injury in mouse and N2a cell damage model. METHODS: First, BMSC surface markers were detected by flow cytometry, followed by extraction of BMSCs-derived exosomes (BMSCs-Exos). A mouse model of neuronal injury was induced by middle cerebral artery occlusion/reperfusion (MCAO/R), and N2a cells were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) for in vitro experiments. BMSCs-Exos were administrated in mice and N2a cells. We subsequently determined viability- and apoptosis-features using EdU staining, CCK-8, flow cytometry and Caspase-3 kits. Subsequently, we used RT-qPCR to assess miR-455-3p expression in brain tissues as well as N2a cells, and bioinformatic tools to predict the targeting mRNA of miR-455-3p, which was validated by dual-luciferase assays. RESULTS: BMSCs-Exos improved hippocampal neuronal injury in MCAO/R-treated mice and OGD/R-induced injury to N2a cells. BMSCs-Exos upregulated miR-455-3p expression in brain tissues of mice and OGD/R-treated N2a cells. miR-455-3p targeted and conversely regulated PDCD7 expression. The protective effect of BMSCs-Exos on OGD/R-treated N2a cells was markedly mitigated following miR-455-3p downregulation. Moreover, overexpression of miR-455-3p contributed to increased N2a cell activity and decreased apoptosis, while the rescue experiment results were opposite. CONCLUSION: MSCs-derived exosomal miR-455-3p targeted PDCD7 to alleviate hippocampal neuronal injury in MCAO/R-treated mice and injury of OGD/R-treated N2a cells.