In central nervous system, a growth factor progranulin (PGRN) is considered to play crucial roles in maintaining physiological functions, and mutations in PGRN gene cause TDP-43-positive frontotemporal lobar degeneration. We demonstrated a dynamic change of PGRN expression in ischemic rats, including increased levels of PGRN expression in microglia within the ischemic core, and those in survived neurons as well as induction of PGRN expression in endothelial cells within the ischemic penumbra. We observed that PGRN could protect against acute focal cerebral ischemia by variety of mechanisms, which we call "brain protection", including neuroprotection in part by inhibition of cytoplasmic redistribution of TDP-43 using PGRN knock-out mice, suppression of neuroinflammation via anti-inflammatory interleukin-10 in microglia, and attenuation of blood-brain barrier disruption via vascular endothelial growth factor. Finally, we demonstrated the therapeutic potential of PGRN against acute focal cerebral ischemia using a rat autologous thromboembolic model with delayed tissue plasminogen activator treatment. Intravenously administered recombinant PGRN significantly reduced volumes of cerebral infarct and edema, suppressed hemorrhagic transformation, and improved motor outcome. PGRN may be a novel therapeutic target that provides brain protection such as vascular protection, anti-neuroinflammation, and neuroprotection. We accelerate further research towards the development of PGRN-based treatments against stroke.