The current study has shown that chronic neurodegeneration, in the ME7 prion disease model, drives a robust STING‐dependent IFN‐I response, Blocking IFN‐I action via deletion of IFNAR1 led to a significant alteration of microglial phenotype, with significant downregulation of a large number of phagocytic, lysosomal, complement, and NADPH oxidase transcripts. Here, IFNAR1 is linked to prion disease.