Synaptic plasticity has been strongly implicated in early stages of neurodegenerative and neurodevelopmental disorders. Here, we describe distinct region-specific patterns of synaptic remodeling across the brain, arising within 1-4 hours of stroke onset. As synapses in the ischemic core decline profoundly, mildly ischemic penumbra retains synaptic structure albeit with decreased function, whereas the contralateral hemisphere shows an increase in synaptic size and function. Mechanistically, stroke leads to synaptic recruitment of NMDA-type glutamate receptors (NMDARs) in ischemic core and penumbra, and NMDAR signaling blockade triggers synaptic loss in the penumbra and abolishes contralateral synaptic enhancement. Proteomic analysis confirms broad synaptic enhancement in the contralateral hemisphere and reveals rapid onset of metabolic rearrangement in the penumbra, while RNAseq shows decline of synaptic gene expression in the penumbra.