Cerebral ischemia-reperfusion damages local brain tissue and impairs brain function, but its specific pathogenesis is still uncertain. Recent studies have clarified circPUM1 is aberrantly elevated in cerebral ischemia-reperfusion injury; however, circPUM1ʹs function in cerebral ischemia-reperfusion-induced neuronal injury remains ambiguous. The results illustrated circPUM1 and DEAD-box helicase 5 were decreased, but microRNA-340-5p was elevated in transient middle cerebral artery occlusion mice and oxygen glucose deprivation/reoxygenation-treated SH-SY5Y cells. Knockdown of circPUM1 aggravated the neuronal injury in transient middle cerebral artery occlusion mice and motivated glial cell activation, neuronal apoptosis and inflammation. Enhancing circPUM1 restrained oxygen glucose deprivation/reoxygenation-induced SH-SY5Y cell apoptosis, the release of lactate dehydrogenase and inflammatory factors, and activation of nuclear factor-kappaB pathway, while elevating microRNA-340-5p aggravated oxygen glucose deprivation/reoxygenation-induced cell damage. Functional rescue experiments exhibited that the impacts of knockdown or enhancement of circPUM1 were turned around by microRNA-340-5p downregulation and DEAD-box helicase 5 silencing, respectively. Moreover, it was demonstrated that circPUM1 competitively adsorbed microRNA-340-5p to mediate DEAD-box helicase 5. All in all, this study clarifies that circPUM1 mitigates cerebral ischemia-reperfusion-induced neuronal injury by targeting the microRNA-340-5p/DEAD-box helicase 5 axis.