Krüppel-like factors (KLFs) belong to the zinc finger family of transcription factors, and their function in the CNS is largely unexplored. KLF11 is a member of the KLF family, and we have previously demonstrated that peroxisome proliferator-activated receptor gamma-mediated cerebral protection during ischemic insults needs recruitment of KLF11 as its critical coactivator. Here, we sought to determine the role of KLF11 itself in cerebrovascular function and the pathogenesis of ischemic stroke. Transient middle cerebral artery occlusion (MCAO) was performed in KLF11 knockout and wild-type control mice, and brain infarction was analyzed by TTC staining. BBB integrity was assessed by using Evans Blue and TMR-Dextran extravasation assays. KLF11 KO mice exhibited significantly larger brain infarction and poorer neurological outcomes in response to ischemic insults. Genetic deficiency of KLF11 in mice also significantly aggravated ischemia-induced BBB disruption by increasing cerebrovascular permeability and edema. Mechanistically, KLF11 was found to directly regulate IL-6 in the brains of ischemic mice. These findings suggest that KLF11 acts as a novel protective factor in ischemic stroke. Elucidating the functional importance of KLF11 in ischemia may lead us to discover novel pharmacological targets for the development of effective therapies against ischemic stroke.