Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common type of dementia worldwide. Pathological factors, such as Aβ deposition and glial cell activation, have been shown to be associated with changes of the glymphatic system, the drainage system of the brain parenchyma. However, the potential roles of astrocyte activity in the early stage of AD remain unclear. In this study, we aimed to investigate the changes in astrocyte activity and its pathological roles in the medial prefrontal cortex (mPFC) of 5xFAD mice at 4-5 months of age with two-photon microscopy, chemogenetic and genetic manipulation. The potential molecular mechanisms were also identified by transcriptomic analysis. To assess brain glymphatic drainage efficiency and AQP4 polarization, we used tracer injection through cisterna magna in combination with 9.4T magnetic resonance imaging or immunofluorescence staining. Our results demonstrated a significant elevation in astrocyte activity in the mPFC. Interestingly, suppressing astrocyte activity resulted in improved glymphatic flow and cognitive function in the 5xFAD mice. Furthermore, astrocyte activation led to significant changes in the metabolic pathway. By intervening in this pathway, we were able to restore the polarity of AQP4 and improve glymphatic flow efficiency, thereby ameliorating cognitive dysfunction in the 5xFAD mice. Overall, our findings provide insights into the abnormal astrocyte activity and its mechanistic consequences in glymphatic drainage and cognitive function during the early pathogenesis of AD.