A paramount driver of sporadic Alzheimer′s disease (AD) is the synergy of oxidative stress and glucose hypometabolism in the brain. Oxidative stress damages macromolecules such as DNA, lipids and proteins, whereas glucose hypometabolism impairs cellular energy supply and antioxidant defense; Together, these cellular and functional alterations may be primary triggers of AD. However, the exact basis of AD-associated glucose hypometabolism has remained unknown. Here we report acute inhibition of brain glucose utilization by beta-amyloid peptide (Aβ1-42) and identify oxidative stress resulting from Aβ1-42 -induced activation of NADPH oxidase 2 (NOX2) as the trigger of brain glucose hypometabolism and network hyperactivity. We show that in hippocampal brain slices, Aβ1-42 application reduced network activity-driven glucose consumption and glycolysis by half, while NOX2 antagonism prevented this effect. In vivo, intracerebroventricular injection of Aβ1-42 exerted a profound inhibitory effect on brain glucose consumption, resulting in long-lasting network hyperactivity and changes in animal behavioral profile. Critically, the novel bioavailable NOX2 antagonist GSK2795039 prevented all of the observed Aβ-related detrimental effects. These data provide the first experimental evidence behind AD-related brain glucose hypometabolism and its consequences, and suggest that targeting NOX2-induced oxidative stress is a promising approach to both the prevention and treatment of AD. ### Competing Interest Statement The authors have declared no competing interest.