Mature retinal ganglion cells like other CNS neurons are unable to regenerate their axons after injury. Regenerative failure has been attributed, in part, to two factors: the existence of myelin-derived inhibitors that bind to the Nogo receptor (NgR) and a deficiency of trophic support factors. We investigated the regrowth of injured axons both by inhibiting NgR by RNA interference and by recruiting exogenous trophic support by zymosan intravitreal injection. Our results showed that either approach can stimulate optic nerve axon regrowth but regenerated axons can grow longer and extend further when both methods are combined. We conclude that endogenous NgR inhibition and exogenous trophic support both play independent, important roles in enhancing optic nerve axon regrowth and that the regenerative effect can be augmented when the two are combined. This may provide a therapeutic strategy for promoting axon regeneration in the CNS as well.