We investigated whether microglial depletion via chronic pharmacological inhibition of colony-stimulating factor 1 receptor (CSF1R) influences tau pathology and behavior in an mouse model of amyloid-enhanced tauopathy. Chronic CSF1R inhibition modestly reduced hippocampal phosphorylated tau and cortical amyloid plaque burden while partially improving cognitive flexibility and anxiety-like behaviors. Homeostatic and disease-associated microglia were more susceptible to depletion than broader myeloid cell populations, suggesting subtype-specific therapeutic vulnerability. Depletion-resistant Mac-2+/Iba1− cells near plaques were also observed, which may represent infiltrating peripheral macrophages. These findings support a mechanistic role for microglia in linking amyloid pathology to tau accumulation and neurodegeneration.