We previously identified that ngr1 allele deletion limits the severity of experimental autoimmune encephalomyelitis (EAE) by preserving axonal integrity. However, whether this favorable outcome observed in EAE is a consequence of an abrogated neuronal-specific pathophysiological mechanism, is yet to be defined. Here we show that, Cre-loxP-mediated neuron-specific deletion of ngr1 preserved axonal integrity, whereas its re-expression in ngr1(-/-) female mice potentiated EAE-axonopathy. As a corollary, myelin integrity was preserved under Cre deletion in ngr1(flx/flx), retinal ganglion cell axons whereas, significant demyelination occurred in the ngr1(-/-) optic nerves following the re-introduction of NgR1. Moreover, Cre-loxP-mediated axon-specific deletion of ngr1 in ngr1(flx/flx) mice also demonstrated efficient anterograde transport of fluorescently-labeled ChTx beta in the optic nerves of EAE-induced mice. However, the anterograde transport of ChTx beta displayed accumulation in optic nerve degenerative axons of EAE-induced ngr1(-/-) mice, when NgR1 was reintroduced but was shown to be transported efficiently in the contralateral non-recombinant adeno-associated virus serotype 2-transduced optic nerves of these mutant mice. We further identified that the interaction between the axonal motor protein, Kinesin-1 and collapsin response mediator protein 2 (CRMP2) was unchanged upon Cre deletion of ngr1. Whereas, this Kinesin-1/CRMP2 association was reduced when NgR1 was re-expressed in the ngr1(-/-) optic nerves. Our data suggest that NgR1 governs axonal degeneration in the context of inflammatory-mediated demyelination through the phosphorylation of CRMP2 by stalling axonal vesicular transport. Moreover, axon-specific deletion of ngr1 preserves axonal transport mechanisms, blunting the induction of inflammatory demyelination and limiting the severity of EAE.