Optic nerve head astrocytes (ONHAs) are the major cell type within the optic nerve head, providing both structural and nutrient support to the optic nerve. Astrocytes are necessary for the survival of neurons with controlled activation of astrocytes being beneficial to neurons. However, overactive astrocytes can be harmful and the loss of normal astrocyte function can be a primary contributor to neurodegeneration. The neuroprotective properties of reactive astrocytes can be lost or they might gain neurotoxic properties in neurodegenerative diseases. The activated astrocytes are crucial in the development of glaucoma, where they serve as a source for cytotoxic substances that participate in ganglion apoptosis. There is increasing evidence indicating that neuroinflammation is an important process in glaucoma. Under pathological conditions, astrocytes can induce an inflammatory response. Extensive evidence shows that inflammatory responses mediated by astrocytes can also influence pathology development, synapse health, and neurodegeneration. The elimination of activated astrocytes by apoptosis is also expected in unfavorable conditions. In neurodegenerative diseases, a common feature is the presence of aggregates found in astrocytes, which can disrupt astrocyte function in such a way as to be detrimental to the viability of neurons. The biological processes involved in vision loss in glaucoma are not well understood. Despite the rapid advances in our understanding of optic nerve head (ONH) structure and function, numerous potential contributions of the ONHAs to optic nerve damage remain unanswered. The present study investigated the role of ONHAs during oxidative stress in order to determine novel cell biological processes underlying glaucoma pathogenesis. ONHAs were exposed to chemically induced oxidative stress using tert-butyl hydroperoxide (tBHP) in order to model extracellular oxidative stress as it occurs in the glaucomatous retina and ONH. In order to determine the impact of an intervention approach employing potential glioprotective treatments for central nervous system tissue we pretreated cells with the polyphenolic phytostilbene and antioxidant trans-resveratrol (3,5,4'-trihydroxy-trans-stilbene). ONHAs exposed to tBHP-mediated oxidative stress displayed decreased viability and underwent apoptosis. In addition, increased levels of activated caspases, dephosphorylation of Tau protein at Ser422, an important site adjacent to the caspase cleavage site controlling Tau cleavage, caspase-mediated Tau cleavage, and cytoskeletal changes, specifically formation of neurofibrillary tangles (NFTs) were detected in ONHAs undergoing oxidative stress. When cells were pretreated with resveratrol cell viability increased along with a significant decrease in activated caspases, cleaved Tau, and NFT formation. Taken together, ONHAs appear to act similar to neurons when undergoing oxidative stress, where proteolytic cleavage of Tau by caspases leads to NFT formation. In addition, resveratrol appears to have promise as a potential protective treatment preventing ONHA dysfunction and degeneration. There is currently no cure for glaucoma or a neuro- and glioprotective treatment that directly targets the pathogenic mechanisms in the glaucomatous retina and optic nerve. The present study identified a potential mechanism underlying degeneration of astrocytes that is susceptible to pharmaco-therapeutic intervention in the eye and potentially elsewhere in the central nervous system. Identification of such mechanisms involved in glaucoma and other disorders of the eye and brain is critical to determine novel targets for effective therapies.