Retinal ganglion cells (RGCs) expanding from the retina to the brain are primary victims of neurodegeneration in glaucoma, a leading cause of blindness; however, the neighboring astroglia survive the glaucoma-related stress and promote neuroinflammation. In light of diverse functions of caspase-8 in apoptosis, cell survival, and inflammation, this study investigated the importance of caspase-8 in different fates of glaucomatous RGCs and astroglia using two experimental approaches in parallel. In the first approach, cell type-specific responses of RGCs and astroglia to a caspase-8 cleavage-inhibiting pharmacological treatment were studied in rat eyes with or without experimentally induced glaucoma. The second approach utilized an experimental model of glaucoma in mice in which astroglial caspase-8 was conditionally deleted by cre/lox. Findings of these experiments revealed cell type-specific distinct processes that regulate caspase-8 functions in experimental glaucoma, which are involved in inducing the apoptosis of RGCs and promoting the survival and inflammatory responses of astroglia. Deletion of caspase-8 in astroglia protected RGCs against glia-driven inflammatory injury, while the inhibition of caspase-8 cleavage inhibited apoptosis in RGCs themselves. Various caspase-8 functions impacting both RGC apoptosis and astroglia-driven neuroinflammation may suggest the multi-target potential of caspase-8 regulation to provide neuroprotection and immunomodulation in glaucoma. Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.