Work over the last decade demonstrates that the myelin sheaths enwrapping axons, classically seen as static insulators, are highly dynamic and respond to axonal activity and experience. This phenomenon, called “myelin plasticity”, goes beyond postnatal stages into adulthood and plays a key role in remodeling neuronal circuits to support adaptive behavior or functional recovery upon injury. Yet the mechanisms are unknown. Here we show that NMDA receptors containing GluN3A subunits are expressed by oligodendrocyte progenitor cells (OPCs) and essentially required for activity-dependent myelin plasticity. Specifically, a functional analysis of constitutive or OPC-restricted Grin3a knockout mice demonstrated that OPCs that lack GluN3A fail to differentiate in response to chemo-genetic stimulation of callossal axons. Similar deficits were observed when OPC responses were triggered using natural paradigms that elicit myelin plasticity, including chronic physical exercise on a treadmill or fine motor training in the Erasmus Ladder. At the behavioral level, selective GluN3A deletion from OPCs impaired motor performance upon challenges. Importantly, the regenerative capacity of OPCs declines with aging, correlating with a significant down-regulation of GluN3A expression and predicting limits in plasticity. In line with this prediction, we find that OPCs from GluN3A knockouts exhibit a molecular signature, with elevated levels of a set of immune-related genes and inflammatory networks that resemble OPC signatures in old mice and disease associated OPCs in experimental autoimmune encephalitis and multiple sclerosis. Our study opens an opportunity to develop strategies to re-express GluN3A and boost myelin plasticity that declines during aging and neurodegenerative diseases.