Neuronal plasticity is critical for the maintenance and modulation of brain activity. Emerging evidence indicates that glial cells actively shape neuroplasticity, allowing for highly flexible regulation of synaptic transmission, neuronal excitability, and network synchronization. Astrocytes regulate synaptogenesis, stabilize synaptic connectivity, and preserve the balance between excitation and inhibition in neuronal networks. Microglia, the brain-resident immune cells, continuously monitor and sculpt synapses, allowing for the remodeling of brain circuits. Glia-mediated neuroplasticity is driven by neuronal activity, controlled by a plethora of feedback signaling mechanisms and crucially involves extracellular matrix remodeling in the central nervous system. This review summarizes the key findings considering neurotransmission regulation and metabolic support by astrocyte-neuronal networks, and synaptic remodeling mediated by microglia. Novel data indicate that astrocytes and microglia are pivotal for controlling brain function, indicating the necessity to rethink neurocentric neuroplasticity views.