AbstractNeuronal hyperactivity is a key feature of early stages of Alzheimer's disease (AD). Genetic studies in AD support that microglia act as potential cellular drivers of disease risk, but the molecular determinants of microglia‐synapse engulfment associated with neuronal hyperactivity in AD are unclear. Here, using super‐resolution microscopy, 3D‐live imaging of co‐cultures, and in vivo imaging of lipids in genetic models, we found that spines become hyperactive upon Aβ oligomer stimulation and externalize phosphatidylserine (ePtdSer), a canonical “eat‐me” signal. These apoptotic‐like spines are targeted by microglia for engulfment via TREM2 leading to amelioration of Aβ oligomer‐induced synaptic hyperactivity. We also show the in vivo relevance of ePtdSer‐TREM2 signaling in microglia‐synapse engulfment in the hAPP NL‐F knock‐in mouse model of AD. Higher levels of apoptotic‐like synapses in mice as well as humans that carry TREM2 loss‐of‐function variants were also observed. Our work supports that microglia remove hyperactive ePtdSer⁺ synapses in Aβ‐relevant context and suggest a potential beneficial role for microglia in the earliest stages of AD.