Alzheimer's disease is a progressive and age-related neurodegenerative disorder that is manifested by neuropathological changes and clinical symptoms. Recently, cell-based therapeutic interventions have been considered as the promising and effective strategies in this field. Herein, we investigated therapeutic effects of neural stem cell secretome on Alzheimer's disease-like model by triggering of Wnt/ß-catenin signaling pathway. In this study, mice were randomly allocated into three different groups as follows: Control, AD + Vehicle, and AD + NSCs-CM groups. To induce mouse model of AD, Aß1-42 was injected into intracerebroventricular region. Following AD-like confirmation through thioflavin S staining and Passive avoidance test, about 5 µl mouse NSCs-CM was injected into the target areas 21 days after AD induction. For evaluation of endogenous proliferation rate (BrdU/Nestin+ cells), 50 µg/kbW BrdU was intraperitoneally injected for 5 consecutive days. To track NSC differentiation, percent of BrdU/NeuN+ cells were monitored via immunofluorescence staining. Histological Nissl staining was done to neurotoxicity and cell death in AD mice after NSCs-CM injection. Morris Water maze test was performed to assess learning and memory performance. Data showed that NSCs-CM could reverse the learning and memory deficits associated with Aß pathology. The reduced expression of Wnt/ß-catenin-related genes such as PI3K, Akt, MAPK, and ERK in AD mice was increased. Along with these changes, NSCs-CM suppressed overactivity of GSK3ß activity induced by Aß deposition. Besides, NSCs increased BrdU/Nestin+ and BrdU/NeuN+ cells in a paracrine manner, indicating proliferation and neural differentiation of NSCs. Moreover, neurotoxicity rate and cell loss were deceased after NSCs-CM injection. In summary, NSCs can regulate adult neurogenesis through modulating of Wnt/ß-catenin signaling pathway and enhance the behavioral performance in the AD mice. These data present the alternative and effective approach in the management of AD and other cognitive impairments.