Modulating the behaviors of reactive astrocytes is a potential therapeutic strategy for neurodegenerative diseases. We found that upregulation and activation of the epidermal growth factor receptor (EGFR) occur in astrocytes after different injuries in optic nerves in vivo. Activation of EGFR regulates genes and cellular processes representing most major markers of reactive astrocytes and genes related with glaucomatous optic neuropathy and other neural disorders. These results suggest that activation of EGFR is a common, regulatory pathway that triggers quiescent astrocytes into reactive astrocytes in response to neural injuries in the optic nerve, and perhaps other parts of the CNS. Targeting EGFR activation using an EGFR tyrosine kinase inhibitor prevents the loss of retinal ganglion cells in a model of glaucomatous optic neuropathy. Because these inhibitors are currently used clinically, our results present an approach to reactive astrocytes as a potential new target for the treatment of neurodegenerations.