Homeostatic regulation of synapses is vital for healthy nervous system function. Activity-dependent synaptic scaling, an intensely studied form of homeostasis, is proposed to operate over hours to counteract the destabilizing influence of long-term potentiation (LTP) and long-term depression (LTD). The prevailing view holds that synaptic scaling is a slow first-order process that regulates postsynaptic glutamate receptors and fundamentally differs from LTP or LTD. Our experiments challenge these presumptions. Surprisingly, the dynamics of scaling induced by neuronal inactivity are not exponential or monotonic and the mechanism requires calcineurin and CaMKII, molecules dominant in LTD and LTP. Our quantitative model of the interplay between these enzymes reconstructs the unexpected dynamics of homeostatic scaling and reveals how synapses efficiently safeguard future capacity for synaptic plasticity on demand. The modeling also provides a framework for understanding Alzheimer’s disease and how calcium dysregulation in AD might cause disruption of synaptic homeostasis. Our human genetics-based experiments in mouse models of Alzheimer’s implicate this kind of pathophysiological connection.