In a zebrafish spinal-root injury model that involves complete severing of a peripheral nerve from the cord, microglia were observed using time-lapse imaging to leave the spinal cord and enter the periphery. Once there, they phagocytose debris from the injury site and re-enter the spinal cord in a morphologically changed state, and were observed to emigrate as far as the brain. This emigration required glutamate-mediated activation of NMDA receptors and was regulated by heterotypic interactions with macrophages. These data reveal that rather than being confined to the CNS, microglia can exit and re-enter central regions.