The mechanisms underlying the chronicity of autoimmune diseases of the central nervous system (CNS) are largely unknown. In particular, it is unclear whether tissue-resident memory T cells (T_RM) contribute to lesion pathogenesis during chronic CNS autoimmunity. Here, we observed that a high frequency of brain-infiltrating CD8⁺ T cells exhibit a T_RM-like phenotype in human autoimmune encephalitis. Using mouse models of neuronal autoimmunity and a combination of T single-cell transcriptomics, high-dimensional flow cytometry, and histopathology, we found that pathogenic CD8⁺ T cells behind the blood-brain barrier adopt a characteristic T_RM differentiation program, and we revealed their phenotypic and functional heterogeneity. In the diseased CNS, autoreactive tissue-resident CD8⁺ T cells sustained focal neuroinflammation and progressive loss of neurons, independently of recirculating CD8⁺ T cells. Consistently, a large fraction of autoreactive tissue-resident CD8⁺ T cells exhibited proliferative potential as well as proinflammatory and cytotoxic properties. Persistence of tissue-resident CD8⁺ T cells in the CNS and their functional output, but not their initial differentiation, were crucially dependent on CD4⁺ T cells. Collectively, our results point to tissue-resident CD8⁺ T cells as essential drivers of chronic CNS autoimmunity and suggest that therapies targeting this compartmentalized autoreactive T cell subset might be effective for treating CNS autoimmune diseases.