NF-κB is dually involved in neurogenesis and brain pathology. Here, we addressed its role in adult axoneogenesis by generating mutations of RelA and p50 heterodimers of canonical NF-κB. In addition to activation in astrocytes, optic nerve axonotmesis caused a hitherto unrecognized RelA induction in growth inhibitory oligodendrocytes. Intraretinally, RelA was induced in severed retinal ganglion cells and inferred in bystander Muller glia. Cell type-specific deletion of transactivating RelA in neurons and/or macroglia considerably stimulated axonal regeneration in a distinct and synergistic pattern. In contrast, deletion of the p50 suppressor subunit promoted spontaneous and post-injury Wallerian degeneration. Growth effects mediated by RelA deletion paralleled a downregulation of growth inhibitory Cdh1 and upregulation of the endogenous Cdh1 suppressor EMI1. Pro-degenerative loss of p50, however, stabilized retinal Cdh1. In vitro, RelA deletion elicited opposing, pro-regenerative shifts in active nuclear and inactive cytoplasmic moieties of Cdh1 and Id2. The involvement of NF-κB and cell cycle regulators such as Cdh1 in regenerative processes of non-replicative neurons presents novel options regarding how molecular reprograming might be executed to stimulate adult axoneogenesis and treat CNS axonopathies.