Diabetic retinopathy (DR) is a devastating sight-threatening complication of diabetes mellitus (DM). Besides damaging the vascular system of the retina, DM will also destruct the tissue surrounding the retina, including the optic nerve. DR impairs the optic nerve by damaging its conduction and integrity. There are few clinical manifestations of optic nerve changes in DR such as diabetic papillopathy, neovascularization of optic disc, and optic nerve atrophy. These involve metabolic alterations related to DM, production of advanced glycation end products (AGEs), oxidative stress, and hemodynamic changes. Diagnostic tests including visual evoked potential (VEP) and optical coherence tomography (OCT) can detect functional and structural changes. This finding is important as it may reflect the early loss of retinal ganglion cell axons. As the neuronal loss is irreversible, it is pivotal to be able to screen these nervous system changes in the early stage of DR and prevent further deterioration.