Dynamin-related protein 1 (Drp1) regulates mitochondrial fission and participates in neuronal apoptosis during the pathology of cerebral ischemia. We have previously shown that inhibition of phosphodiesterase-4 (PDE4) protects against neuronal apoptosis in models of ischemic stroke. However, it remains unclear whether PDE4 inhibition affects Drp1-mediated mitochondrial dysfunction and apoptosis under cerebral ischemia conditions. This study aimed to determine whether ZX21011, a novel PDE4 inhibitor synthesized in our laboratory, can act on Drp1 to counteract ischemic brain injury and to elucidate its mechanism of action. We demonstrated that ZX21011 effectively reduced neuronal apoptosis caused by oxygen-glucose deprivation/reoxygenation (OGD/R) in HT22 cells and ameliorated neurological deficits caused by middle cerebral artery occlusion/reperfusion (MCAO/R) in rats. ZX21011 enhanced glycogen synthase kinase-3β (GSK3β) phosphorylation (Ser9), GSK3β(S9A) mutation blocked the protective effects of ZX21011. Simultaneously, ZX21011 reduced the levels of reactive oxygen species (ROS), restored the morphology of mitochondria, and inhibited the phosphorylation of Drp1(Ser616). The Drp1(S616E) mutation blocked the protective effects of ZX21011 on ROS production and mitochondrial morphology function after cerebral ischemia. What's more, co-immunoprecipitation analysis revealed that ZX21011 decreased the binding of GSK3β to Drp1, and GSK3β(S9A) mutation reversed the effects of ZX21011 on Drp1 phosphorylation and cell viability. Moreover, ZX21011 decreased Drp1(Ser616) phosphorylation within the ischemic penumbra of rats following cerebral ischemia/reperfusion. In summary, ZX21011 counteracts ischemic stroke-induced oxidative stress and neuronal death, and its action is related to decreased Drp1 phosphorylation at Ser616. Thus, ZX21011 is a potential compound for the intervention of stroke.