Prion diseases, also known as transmissible spongiform encephalopathies, are a group of fatal, transmissible neurodegenerative disorders affecting both humans and animals, with no available therapeutic treatments. Recent research highlights the critical involvement of reactive microglia and astrocytes in the pathogenesis of these diseases. This chapter will review emerging evidence on the harmful roles of reactive microglia and astrocytes in prion disease progression and explore potential therapeutic strategies aimed at targeting their reactive states. A particular focus will be on the therapeutic potential of modulating microglial phagocytic activity and its associated pathways. We will address the challenges in designing effective therapies, including the phenotypic diversity of glial cells, regional differences in brain strain tropism, intercellular communication between microglia and astrocytes, dynamic changes in microglial role throughout disease progression, and the identification of optimal intervention windows. Finally, we will consider the possibility that different mechanisms underlie neurodegeneration across prion strains and Creutzfeldt-Jakob disease (CJD) subtypes, highlighting the importance of developing combination therapies targeting multiple pathways.