Despite a dramatic increase in ischemic stroke incidence worldwide, effective therapies for attenuating sequelae of cerebral infarction are lacking. This study investigates the use of human mesenchymal stem cells (hMSCs) induced toward glia-like cells (ghMSCs) to ameliorate chronic sequelae resulting from cerebral infarction. Transcriptome analysis demonstrated that ghMSCs exhibited astrocytic characteristics, and assessments conducted ex vivo using organotypic brain slice cultures demonstrated that ghMSCs exhibited superior neuroregenerative and neuroprotective activity against ischemic damage compared to hMSCs. The observed beneficial effects of ghMSCs were diminished by pre-treatment with a CXCR2 antagonist, indicating a direct role for CXCR2 signaling. Studies conducted in rats subjected to cerebral infarction demonstrated that ghMSCs restored neurobehavioral functions and reduced chronic brain infarction in a dose-dependent manner when transplanted at the subacute-to-chronic phase. These beneficial impacts were also inhibited by a CXCR2 antagonist. Molecular analyses confirmed that increased neuroplasticity contributed to ghMSCs' neuroregenerative effects. These data indicate that ghMSCs hold promise for treating refractory sequelae resulting from cerebral infarction by enhancing neuroplasticity and identify CXCR2 signaling as an important mediator of ghMSCs' mechanism of action.