Neonatal hypoxia-ischemia is a severe condition that can result in death and/or lifelong central nervous system sequelae. Benefits of cannabidiol (CBD) result from neuroprotection asssumed to be mainly due to targeting a variety of neuronal receptors. The results of this article first show that CBD protects both primary neurons and primary glia against death induced by glucose and oxygen deprivation. Second, the expression of glial markers in an animal model of neonatal hypoxia-ischemia treated with vehicle or CBD shows that the cannabinoid was able to skew microglia towards a neuroprotective phenotype. Of interest was the expression of markers of neuroprotection in the microglia of lesioned animals. The microglia-mediated neuroprotection mechanism provided by CBD appears to be the increased expression of neuroprotective markers and the marked reduction in the release of proinflammatory factors from microglia activated by hypoxic-ischemic damage.