Background: Ischemic stroke is significantly affected by the dysfunction of the miRNA network. Recent research has described that disordered expression of miR-130a is associated with ischemic stroke. Here, we aimed to investigate the possible mechanism of the miR-130a-mediated neuroprotection that follows ischemia-reperfusion (I/R) injury. Method: This study was comprised of two models: oxygen-glucose deprivation/Reperfusion (OGDR) and middle cerebral artery occlusion (MCAO). RT-PCR and immunoblotting were used to examine gene expression levels, and MTT assay and flow cytometric analysis were used to examine cell states. We also used 2, 3, 5-triphenyltetrazolium chloride (TTC) staining to assess the cerebral infarct volume. Then, we employed bioinformatics analysis and luciferase reporter assay to identify and validate the target molecule of miR-130a, PTEN. Results: Our findings indicated that miR-130a expression was lower in PC12 cells after OGDR (oxygen-glucose deprivation/reperfusion) and in rats after MCAO (middle cerebral artery occlusion). Moreover, ectopic-expression of miR-130a can significantly improve cell survival rate and reduce cell apoptosis and ROS production in PC12 cells after OGDR. In addition, re-expression of miR-130a yielded an obvious reduction in MCAO-induced infarct volume and neurological deficits in rats. Bioinformatics analysis revealed that PTEN was a miR-130a target and could overturn the effect of miR-130a on cerebral ischemia, both in vivo and in vitro. Therefore, we set out to further investigate the PTEN-affected PI3K/AKT pathway and found that upregulation of miR-130a activated the PI3K/AKT pathway. Conclusions: Our data demonstrated that miR-130a prevented cerebral I/R damage by mediating the PTEN/PI3K/AKT axis. These preliminarily findings furthered our understanding of this mechanism and identified new potential therapeutic targets for ischemic stroke.