Prion diseases are transmissible, neurodegenerative disorders to which there are no cures. Previous studies show that reduction of microglia accelerates prion disease and increases the accumulation of prions in the brain, suggesting that microglia provide neuroprotection by phagocytosing and destroying prions. In Csf1rΔFIRE mice, the deletion of an enhancer within Csf1r specifically blocks microglia development, however, their brains develop normally with none of the deficits reported in other microglia-deficient models. Csf1rΔFIRE mice were used as a refined model to study the impact of microglia-deficiency on CNS prion disease. Although Csf1rΔFIRE mice succumbed to prion disease much earlier than wild-type mice, the accumulation of prions in their brains was reduced. Instead, astrocytes displayed earlier, non-polarized reactive activation with enhanced synaptic pruning and unfolded protein responses. Our data suggest that rather than engulfing and degrading prions, the microglia instead provide neuroprotection and restrict the harmful activities of reactive astrocytes.