Common risk factors for many ocular pathologies involve non-pathologic, age-related damage to the optic nerve. Understanding the mechanisms of age-related changes can facilitate targeted treatments for ocular pathologies that arise at any point in life. In this review, we examine these age-related, neurodegenerative changes in the optic nerve, contextualize these changes from the anatomic to the molecular level, and appreciate their relationship with ocular pathophysiology. From simple structural and mechanical changes at the optic nerve head (ONH), to epigenetic and biochemical alterations of tissue and the environment, multiple age-dependent mechanisms drive extracellular matrix (ECM) remodeling, retinal ganglion cell (RGC) loss, and lowered regenerative ability of respective axons. In conjunction, aging decreases the ability of myelin to preserve maximal conductivity, even with “successfully” regenerated axons. Glial cells, however, regeneratively overcompensate and result in a microenvironment that promotes RGC axonal death. Better elucidating optic nerve neurodegeneration remains of interest, specifically investigating human ECM, RGCs, axons, oligodendrocytes, and astrocytes; clarifying the exact processes of aged ocular connective tissue alterations and their ultrastructural impacts; and developing novel technologies and pharmacotherapies that target known genetic, biochemical, matrisome, and neuroinflammatory markers. Management models should account for age-related changes when addressing glaucoma, diabetic retinopathy, and other blinding diseases.