Astrocytes play essential roles in neuropathology. Human astrocytes exhibit unique properties, highlighting the importance of studying astrocytic responses in human models. Varicose projection astrocytes, previously considered exclusive to hominoids and a physiological type of astrocytes, were suggested to reflect pathological burden, albeit direct evidence linking them to neurological diseases has been lacking. Here, we demonstrate that varicose projection astrocytes also appear in other mammals and show, from four distinct human-based disease models, that varicose projection astrocytes are induced by neuroinflammation and characterized by distinctive subcellular features, indicating involvement in cellular stress responses, and their density is increased in aging and human neuropathology. Our findings establish varicose projection astrocytes as a reactive phenotype associated with neuropathology.