Microglia are phagocytes responsible for the homeostasis and immune responses in the central nervous system (CNS). Peripheral nerve injury (axotomy) models have greatly contributed to our understanding of microglial response to neurodegeneration. Here we established the first avulsion axotomy model in zebrafish. Using in vivo confocal imaging we have characterized the long-term dynamics of microglia-neuron interactions in response to peripheral nerve injury.In vivo time-lapse imaging confirmed that peripheral nerve injury triggered a microglial response in the CNS. This response was characterized by an increased number of microglia displaying rod-like morphology and reduced motility. Microglia engaged in prolonged interactions (12+ hours) with injured neurons, often forming specialized structures that established intimate connections with neuronal somas. Microglia underwent dynamic and morphological changes, indicating a novel microglial response to axotomy-induced neurodegeneration. Using CRISPR-Cas9 and CSF1R-blockage, we modulated microglial function to investigate the signalling pathways involved in this response. Finally, adopting a correlative light and electronic microscopy (CLEM), we reveal the ultrastructure of these interactions.Microglia are crucial in maintaining CNS homeostasis. However, how microglia contribute to neuron survival or shaping of the circuitry in the adult CNS remains elusive. Our results identify an unprecedented microglial response to peripheral nerve injury that may affect neuron viability. Understanding these morphophysiological traits of microglia-neuron interactions provides fundamental new knowledge how the CNS maintains its health.