The toxicity of amyloid-beta (Aβ) is strongly associated with Alzheimer's disease (AD), which has a high incidence in the elderly worldwide. Recent evidence showed that alteration in the activity of N-methyl-D-aspartate receptors (NMDARs) plays a key role in Aβ-induced neurotoxicity. However, the activation of synaptic and extrasynaptic NMDARs has distinct consequences for plasticity, gene regulation, neuronal death, and Aβ production. This review focuses on the dysregulation of synaptic and extrasynaptic NMDARs induced by Aβ. On one hand, Aβ downregulates the synaptic NMDAR response by promoting NMDAR endocytosis, leading to either neurotoxicity or neuroprotection. On the other hand, Aβ enhances the activation of extrasynaptic NMDARs by decreasing neuronal glutamate uptake and inducing glutamate spillover, subsequently causing neurotoxicity. In addition, selective enhancement of synaptic activity by low doses of NMDA, or reduction of extrasynaptic activity by memantine, a non-competitive NMDAR antagonist, halts Aβ-induced neurotoxicity. Therefore, future neuroprotective drugs for AD should aim at both the enhancement of synaptic activity and the disruption of extrasynaptic NMDAR-dependent death signaling.