Microglia are a fundamental component of pathogenesis in many neurological conditions and have specialized functions that vary by disease stage or specific pathology. Drugs targeting colony-stimulating factor-1 receptor (CSF1R) to block microglial proliferation in preclinical disease models have shown mixed outcomes, thus the therapeutic potential of this approach remains unclear. Here, we evaluated CSF1R inhibitors in tauopathy mice using multiple dosing schemes, drug analogs, and longitudinal measurements in the brain and plasma. In both spontaneous disease and in tau fibril inoculation models, we found a region-dependent reduction in insoluble phosphorylated tau and replication-competent tau in mice treated with CSF1R inhibitors. Surprisingly, despite greater drug exposure and microglial depletion in male mice, we observed a rescue of aberrant behavior, reduced plasma neurofilament light chain, and extended survival in female mice only. Gene expression patterns in CSF1R inhibitor-treated tauopathy mice reverted toward a normal wildtype signature, and in vivo imaging revealed suppressed astrogliosis. However, we observed drug dose-dependent upregulation of immediate early genes in male mice only, indicating excitotoxicity, which may have masked functional benefits. Drug-resilient microglia in tauopathy mice exhibited a ramified morphology similar to wildtype microglia but with greater territory occupied per cell, and their transcriptome was neither disease-associated nor homeostatic, suggesting a unique microglial subtype. Our data argue that complete or continuous microglial ablation is neither required nor desired for neuroprotection, and that selective depletion of detrimental, tauopathy-activated microglia may be achieved by precise timing and dosing of CSF1R inhibitors. Importantly, therapeutics targeting microglia must consider sex-dependent effects on functional outcomes when weighing their translational potential for neurological disease.