Mice lacking epidermal growth factor receptor (EGFR) develop a neurodegeneration of unknown etiology affecting exclusively the frontal cortex and olfactory bulbs. Here, we show that EGFR signaling controls cortical degeneration by regulating cortical astrocyte apoptosis. Whereas EGFR^−/− midbrain astrocytes are unaffected, mutant cortical astrocytes display increased apoptosis mediated by an Akt‐caspase‐dependent mechanism and are unable to support neuronal survival. The expression of many neurotrophic factors is unaltered in EGFR^−/− cortical astrocytes suggesting that neuronal loss occurs as a consequence of increased astrocyte apoptosis rather than impaired secretion of trophic factors. Neuron‐specific expression of activated Ras can compensate for the deficiency of EGFR^−/− cortical astrocytes and prevent neuronal death. These results identify two functionally distinct astrocyte populations, which differentially depend on EGFR signaling for their survival and also for their ability to support neuronal survival. These spatial differences in astrocyte composition provide a mechanism for the region‐specific neurodegeneration in EGFR^−/− mice.