Astrocytic dysfunction is closely associated with nearly all types of neurological diseases. Targeting astrocyte regulation has thus emerged as an important potential therapeutic strategy for neurological disorders. However, mechanisms that induce astrocyte dysfunction under pathological conditions have not been fully elucidated. In this study, we identified that Homeodomain-only protein X (Hopx) is downregulated in astrocytes across inflammatory models, Alzheimer's disease (AD) mouse models, and brain tissues from AD patients. In the brains of AD mice, Hopx-positive astrocytes exhibit efficient {beta}-amyloid (A{beta}) plaque clearance, while knockout of Hopx leads to astrocytic dysfunction. Conversely, astrocyte-specific overexpression of Hopx not only significantly enhances their A{beta}; phagocytic function but also effectively reduces the generation of neurotoxic astrocytes while increasing protective astrocytes. In summary, this study demonstrates the core regulatory mechanism underlying astrocytic dysfunction under AD pathological conditions and provides important potential targets for developing therapeutic strategies for AD by targeting astrocyte regulatory pathways.