Brain ischemia disrupts endoplasmic reticulum (ER) dynamics, causes ER stress, and triggers the unfolded protein response (UPR). During the UPR, protein kinase RNA-like ER kinase (PERK) phosphorylates eIF2α, shutting down global protein synthesis, inhibits protein synthesis, and provides neuroprotection during acute ischemic stroke. Herein, middle cerebral artery occlusion/reperfusion (MCAO/R) and PERK neuron-specific deletion conditional knockout mice were employed to observe the function and mechanisms of PERK. CCT020312, a novel selective PERK activator, specifically activates PERK and provides neuroprotection both in vivo and in vitro stroke models. Additionally, CCT020312 enhanced neuronal survival and cerebral microvessels and decreased the level of astrogliosis in acute ischemic stroke mice. Furthermore, in vivo experiments demonstrated that CCT020312 not only prevented apoptosis but also enhanced the PERK/p-eIF2α/LC3-II autophagy signaling pathway in MCAO/R mice. In conclusion, our study supports the potential therapeutic value of targeting PERK in acute ischemic stroke, offering a promising strategy for enhancing stroke outcomes through the modulation of protein synthesis and the autophagy pathway.