Aquaporin-4 (AQP4), the most abundant aquaporin in the brain, is polarized at the glial end-feet facing peri-synaptic areas. AQP4 has been hypothesized to modulate water and potassium fluxes associated with neuronal activity in pathophysiological states. However, the role of AQP4 in astroglial signaling under physiological conditions is unclear. Herein, AQP4 knockout mice and wild-type littermates were tested in the Morris water maze (MWM), which allows for investigating the role of AQP4 in long-term learning and memory. Compared with wild-type mice, AQP4 knockout mice appeared actually to find the platform more easy, but to forget more quickly, in the MWM, indicating that AQP4 knockout mice exhibited impaired memory consolidation in MWM. Moreover, the deficits of memory consolidations were associated with defects in theta-burst stimulation-induced long-term potentiation both in vivo and in vitro. Furthermore, AQP4 knockout mice were accompanied by a decrease in the incorporation of adult-generated granule cells into spatial memory networks. Taken together, our findings indicate that AQP4 plays a modulatory role in memory consolidation. Targeting glial AQP4 may be a new therapeutic strategy for neurodegenerative disorders and related memory impairment.