PURPOSE. Optic neuritis is a condition defined by autoimmune-mediated demyelination of the optic nerve and death of retinal ganglion cells. SIRT1 and NRF2 stimulate anti-inflammatory mechanisms and have previously demonstrated therapeutic value in preclinical models of neurodegenerative disease. Here we investigated the neuroprotective potential of SIRT1 or NRF2 gene transfer using adeno-associated virus (AAV) vectors in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. METHODS. C57Bl/6J mice were administered intravitreal doses of AAV2 vectors and immunized to induce EAE symptoms. Visual function was examined by recording the optokinetic response (OKR) just prior to EAE induction and once every 7 days postinduction for 7 weeks. Retina and optic nerves were harvested to investigate retinal ganglion cell survival (immunolabeling with Brn3a antibodies); inflammation (hematoxylin and eosin staining); and demyelination (luxol fast blue staining). RESULTS. Animals modeling EAE demonstrate reduced visual acuity compared to sham-induced controls. Intravitreal delivery of AAV2-NRF2 did not preserve visual function. However, AAV2-SIRT1 mediated significant preservation of the OKR compared to AAV2-eGFP controls. Treatment with AAV2-NRF2 promoted RGC survival while AAV2-SIRT1 mediated an upward trend in protection compared to vehicle and AAV2-eGFP controls. Neither NRF2 nor SIRT1 gene augmentation was able to suppress optic nerve inflammation or demyelination. CONCLUSIONS. AAV-mediated overexpression of NRF2 or SIRT1 within RGCs mediates distinct neuroprotective effects upon visual function and RGC survival. This study expands our understanding of SIRT1 and NRF2-mediated neuroprotection in the context of MS pathogenesis and optic neuropathies.