We demonstrated that pharmacological activation of aquaporin-4 (AQP4) with TGN-073 enhances glymphatic function and attenuates pathological tau accumulation, neuronal loss, and gliosis in a mouse model of tauopathy. These beneficial effects were abolished in AQP4-deficient mice, highlighting AQP4-mediated glymphatic modulation as a potential therapeutic strategy for tauopathies.