Abstract: The neonatal hypoxic-ischemic encephalopathy (HIE) is an important cause of neurological morbidity and mortality in neonates. Cell therapy is considered a promising method for treating severe neurological disorders such as this one. Stem cells have the capacity for self-renewal and differentiation into certain cell lineages. The present study was aimed to find out the most beneficial route of bone marrow derived mesenchymal stem cells (BMSCs) administration for the attenuation of experimentally induced HIE in neonatal rats. Sixty neonatal rats were divided randomly into four groups. Group I: control group. Group II: rats were exposed to bilateral ligation of cephalic arteries. Group ΙIΙ: rats were exposed to bilateral ligation of cephalic arteries and then underwent intravenous (i.v.) BMSCs injection. Group ΙV: rats were exposed to bilateral ligation of cephalic arteries and then underwent intracerebroventricular (I.C.V) BMSCs injection. The animals were evaluated by (a) neurobehavioral tests; (b) histopathology, i.e. histological and immuno-histochemical studies; and (3) gene expression studies. The BMSCs treated groups (III and IV) showed improvement in neurobehavioral tests, histopathological studies, and gene expression, as compared to non-injected lesioned rats (group II) with better improvement in group IV (I.C.V. injections) than in group III (i.v. injections).