Ischemic stroke often induces profound white matter lesions, resulting in poor neurological outcomes and impaired post-stroke recovery. The present study aimed to investigate the effects of cornel iridoid glycoside (CIG), a major active component extracted from Cornus officinalis, on the white matter injury induced by ischemic stroke and further investigate its neuroprotective mechanisms. Adult male Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO) surgery for 2 h, followed by reperfusion. Rats were intragastrically administered CIG (60 mg/kg and 120 mg/kg) beginning 6 h afters reperfusion, once daily for seven days. A series of behavioral tests (modified neurological severity scores test, object recognition test, adhesive removal test, and beam walking test) were performed to evaluate the neurological functioning in MCAO rats. Histology of the white matter was studied using luxol fast blue staining and transmission electron microscopy. Immunohistochemical staining was performed to assess myelin loss, oligodendrocyte maturation, and glial activation. Activation of the brain-derived neurotrophic factor (BDNF)/neuregulin-1 (NRG1) pathway was evaluated by Western blotting. CIG treatment remarkably decreased the neurological deficit score, accelerated the recovery of somatosensory and motor functions, and ameliorated the memory deficit in MCAO rats. Furthermore, CIG alleviated white matter lesions and demyelination, increased myelin basic protein expression and the number of mature oligodendrocytes, and decreased the number of activated microglia and astrocytes in the corpus callosum of MCAO rats. In addition, Western blot analysis indicated that CIG increased the expression of BDNF/p-TrkB, NRG1/ErbB4 proteins, which further elevated PI3K p110α/p-Akt/p-mTOR signaling in the corpus callosum of MCAO rats. We demonstrated that CIG protects against white matter lesions induced by cerebral ischemia partially by decreasing the number of activated microglia and astrocytes, increasing BDNF level, and activating NRG1/ErbB4 and its downstream PI3K/Akt/mTOR pathways in the white matter. CIG might be used as a potential neuroprotective agent for the treatment of ischemic stroke. © 2019 Wang et al.