Myelination in the CNS is essential for neuronal function, and oligodendrocytes achieve this by wrapping axons with multilayered myelin sheaths. We identify FBXW7 as a key regulator of this process, acting through stage-specific control of oligodendrocyte development and by limiting MYRF activity to prevent pathological myelin overgrowth. These findings position FBXW7 as a critical integrator of transcriptional and proteostatic mechanisms that safeguard myelin structure and neural circuit integrity.