Alzheimer's disease (AD) is a neurodegenerative disorder with progressive memory loss resulting in dementia. Amyloid-beta (Aβ) peptides play a critical role in the pathogenesis of this disease, and are thought to promote inflammation and oxidative stress leading to neurodegeneration in the neocortex and hippocampus of the AD brains. AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis, and cell survival in response to inflammation and oxidative stress. However, the neuroprotective mechanisms by which AMPK achieves these beneficial effects in human neural stem cells (hNSCs) exposed to Aβ is still not well understood. Resveratrol is a potent activator of AMPK suggesting it may have therapeutic potential against AD. Therefore, we will test the hypothesis that the AMPK activator resveratrol protects against Aβ mediated neuronal impairment (inflammation and oxidative stress) in hNSCs. Here, Aβ-treated hNSCs had significantly decreased cell viability that correlated with increased TNF-α and IL-1β inflammatory cytokine expression. Co-treatment with resveratrol significantly abrogated the Aβ-mediated effects in hNSCs, and was effectively blocked by the addition of the AMPK-specific antagonist (Compound C). These results suggest the neuroprotective effects of resveratrol are mediated by an AMPK-dependent pathway. In addition, resveratrol rescued the transcript expression levels of inhibitory kappa B kinase (IKK) in Aβ-treated hNSCs. NF-κB is a transcription factor with a key role in the expression of a variety of genes involved in inflammatory responses. Resveratrol prevented the Aβ-mediated increases in NF-κB mRNA and protein levels, and its nuclear translocation in hNSCs. Co-treatment with resveratrol also significantly restored iNOS and COX-2 levels in Aβ-treated hNSCs. Furthermore, hNSCs co-treated with resveratrol were significantly rescued from Aβ-induced oxidative stress, which correlated with reversal of the Aβ-induced mRNA decrease in oxidative defense genes (SOD-1, NRF2, Gpx1, Catalase, GSH and HO-1). Taken together, these novel findings show that activation of AMPK-dependent signaling by resveratrol rescues Aβ-mediated neurotoxicity in hNSCs, and provides evidence supporting a neuroprotective role for AMPK activating drugs in Aβ-related diseases such as AD.