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Destruction of oligodendrocytes and myelin sheaths in cortical gray matter profoundly alters neural activity and is associated with cognitive disability in multiple sclerosis (MS). Myelin can be restored by regenerating oligodendrocytes from resident progenitors; however, it is not known whether regeneration restores the complex myelination patterns in cortical circuits. Here, we performed time lapse in vivo two photon imaging in somatosensory cortex of adult mice to define the kinetics and specificity of myelin regeneration after acute oligodendrocyte ablation. These longitudinal studies revealed that the pattern of myelination in cortex changed dramatically after regeneration, as new oligodendrocytes were formed in different locations and new sheaths were often established along axon segments previously lacking myelin. Despite the dramatic increase in axonal territory available, oligodendrogenesis was persistently impaired in deeper cortical layers that experienced higher gliosis. Repeated reorganization of myelin patterns in MS may alter circuit function and contribute to cognitive decline.