Significance Throughout an organism’s life span, neural circuits mediate sensory and cognitive processing via synaptic plasticity, which involves synapse-specific Hebbian plasticity and network-level homeostatic plasticity. Synaptic strengthening and weakening are finely tuned by changes in postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) -type glutamate receptors (AMPARs). We have elucidated a biochemical regulation of AMPARs that is specific to homeostatic synaptic plasticity while sparing Hebbian plasticity mechanisms. Specifically, phosphorylation of the AMPAR subunit, GluA2, at tyrosine-876 is required for homeostatic synaptic strengthening by dictating GluA2 binding to glutamate receptor interacting protein 1 (GRIP1), a scaffolding protein crucial for synaptic upscaling. This finding elucidates a mechanism through which neurons can maintain a range of synaptic signaling while not compromising their responsiveness to subsequent synaptic activity.