AbstractObjectiveProgesterone receptor membrane component 2 (PGRMC2) belongs to the membrane‐associated progesterone receptor family, which regulates multiple pathophysiological processes. However, the role of PGRMC2 in ischemic stroke remains unexplored. The present study sought to determine the regulatory role of PGRMC2 in ischemic stroke.MethodsMale C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAO). The protein expression level and localization of PGRMC2 were examined by western blotting and immunofluorescence staining. The gain‐of‐function ligand of PGRMC2 (CPAG‐1, 45 mg/kg) was intraperitoneally injected into sham/MCAO mice, and brain infarction, blood–brain barrier (BBB) leakage, and sensorimotor functions were evaluated by magnetic resonance imaging, brain water content, Evans blue extravasation, immunofluorescence staining, and neurobehavioral tests. The astrocyte and microglial activation, neuronal functions, and gene expression profiles were revealed by RNA sequencing, qPCR, western blotting, and immunofluorescence staining after surgery and CPAG‐1 treatment.ResultsProgesterone receptor membrane component 2 was elevated in different brain cells after ischemic stroke. Intraperitoneal delivery of CPAG‐1 reduced infarct size, brain edema, BBB leakage, astrocyte and microglial activation, and neuronal death, and improved sensorimotor deficits after ischemic stroke.ConclusionCPAG‐1 acts as a novel neuroprotective compound that could reduce neuropathologic damage and improve functional recovery after ischemic stroke.