Traumatic brain injury (TBI) is a leading cause of death and disability worldwide and has been established as a risk factor for neurodegenerative diseases such as Alzheimer’s disease (AD). Neurofibrillary tangles (NFTs), aggregates of intracellular tau, are hallmarks of AD and are observed in the post-TBI brain; however, the mechanisms that contribute to tau aggregation and accumulation are not well understood. One key mechanism that may contribute to this tau aggregation is decreased clearance by the glymphatic system, a perivascular pathway that clears solutes, including tau, from the brain. PS19 mice with tau pathology were crossed with Aqp4-/- mice lacking the astroglial water channel aquaporin-4 (AQP4) or Snta1-/- mice lacking perivascular localization of AQP4. Behavioral tests were performed on the PS19:Aqp4 transgenic crosses at 4 or 6 months of age. Brain tissue was collected and stained for markers of phosphorylated-tau (p-tau) pathology. Sham or mild TBIs were performed on PS19:Snta1 transgenic crosses at 3 months of age. I performed behavioral testing at 4 months (1 month post-TBI) or 6 months (3 month post-TBI). Brain tissue was collected and stained for markers of p-tau pathology. I imaged this immunostained tissue and quantified the pathological tau burden. I observed that Aqp4 deletion was sufficient to exacerbate tau pathology in PS19 mice at 6 months old, in the absence of TBI, and more advanced tau pathology was observed in PS19+Snta1-/- mice at 6 months old (3 months post-TBI) compared to PS19+Snta1+/+ that also received a TBI. Loss of AQP4 or loss of perivascular AQP4 promotes tau pathology in a mouse model of tau pathology. These studies may provide a mechanistic basis for the vulnerability of the post-traumatic brain to tau aggregation and neurodegeneration and suggest that targeting glymphatic dysfunction may be useful in the prevention and treatment of neurodegeneration.