Alzheimer disease (AD) is a neurodegenerative disorder characterized by pathological hallmarks of neurofibrillary tangles and amyloid plaques. The plaques are formed by aggregation and accumulation of amyloid β (Aβ), a cleavage fragment of amyloid precursor protein (APP). Enhanced neuronal activity and seizure events are frequently observed in AD, and elevated synaptic activity promotes Aβ production. However, the mechanisms that link synaptic hyperactivity to APP processing and AD pathogenesis are not well understood. We previously found that Polo-like kinase 2 (Plk2), a homeostatic repressor of neuronal overexcitation, promotes APP β-processing in vitro. Here, we report that Plk2 stimulates Aβ production in vivo, and that Plk2 levels are elevated in a spatiotemporally regulated manner in brains of AD mouse models and human AD patients. Genetic disruption of Plk2 kinase function reduces plaque deposits and activity-dependent Aβ production. Furthermore, pharmacological Plk2 inhibition hinders Aβ formation, synapse loss, and memory decline in an AD mouse model. Thus, Plk2 links synaptic overactivity to APP β-processing, Aβ production, and disease-relevant phenotypes in vivo, suggesting that Plk2 may be a potential target for AD therapeutics.