We identified the chemokine CXCL10 as a contributor of tauopathy pathology. Spatial transcriptomics revealed CXCL10 upregulation in disease-associated astrocytes and microglia within the inflammatory brain environment. Notably, CXCL10 deficiency suppressed tau pathology accumulation and extended survival, but only in females—suggesting CXCL10 is a female-specific contributor of tauopathy progression, with implications for understanding sex differences in neurodegenerative disease and future therapeutic development.