The neurons of our central nervous system are unable to regenerate axons following injury. Regeneration can be promoted by certain manipulations, including knockdown of the Pten phosphatase, but axons still stall before reaching their targets. Ephraim Trakhtenberg and colleagues suspected that newly formed oligodendrocytes (NFOs) could contribute to axonal failure to regenerate, because, developmentally, NFOs appear after axons have grown to their full length (at which point they begin to be myelinated by NFOs); however, after injury, NFOs appear while axons are still growing. Here, they induce optic nerve injury in mice, and use RNA-sequencing and immunohistology to follow changes in the oligodendrocyte population. They find that most existing oligodendrocytes are killed, and the injury site is subsequently repopulated by NFOs largely produced after wounding. They find that inducing optic nerve injury alongside a demyelination regimen reduces the ability of post-injury born NFOs to populate the injury site. This creates an environment where regenerating axons are less likely to interact with NFOs, and they show that stimulating axon regeneration under these conditions produces longer axons. Single-cell RNA-sequencing shows that the NFOs express membrane proteins known to inhibit axon growth, which could explain this effect. Together, this work demonstrates that NFOs contribute to axon regeneration inhibition, which has potential implications for future therapy development.