Previous studies have demonstrated that miR-10b-3p is significantly downregulated in rats after cerebral ischemia injury, and this study aimed to investigate the effect of miR-10b-3p in cerebral ischemia/reperfusion (I/R) injury. The oxygen-glucose deprivation (OGD) induced SH-SY5Y cell model and middle cerebral artery occlusion model (MCAO) rats were constructed to investigate the role of miR-10b-3p and underline the regulatory mechanism of miR-10b-3p/PDCD5 axis in cerebral I/R injury. The expression of miR-10b-3p and PDCD5 was evaluated by qRT-PCR and Western blot. The binding relationship between miR-10b-3p and PDCD5 was determined by bioinformatic analysis and luciferase reporter assay. Cell proliferation was evaluated by MTT assay and Edu staining assay. The apoptosis was assessed by TUNEL staining assay and flow cytometry. MiR-10b-3p was significantly downregulated and PDCD5 was upregulated both in OGD/R induced SH-SY5Y cells and the brain tissues of MCAO/R rats. Luciferase reporter assay determined that miR-10b-3p could directly bind to the 3' UTR of PDCD5 and negatively regulate its expression. MiR-10b-3p overexpression could efficiently inhibit cell viability and proliferation, induce apoptosis of OGD/R-induced SH-SY5Y cells in vitro, and attenuate cerebral I/R injury of MCAO rats in vivo. Silencing of PDCD5 showed similar effect to miR-10b-3p mimics, while PDCD5 overexpression significantly reversed the protective effects of miR-10b-3p mimics on cerebral I/R injury. In summary, our results revealed that miR-10b-3p alleviated cerebral I/R injury partly through targeting PDCD5 and indicated that miR-10b-3p might be a potential target for ischemic stroke.