p58IPKis a multifaceted endoplasmic reticulum (ER) chaperone and a regulator of eIF2α kinases involved in a wide range of cellular processes including protein synthesis, ER stress response, and macrophage-mediated inflammation. Systemic deletion of p58IPKleads to age-related loss of retinal ganglion cells (RGC) and exacerbates RGC damage induced by ischemia/reperfusion and increased intraocular pressure (IOP), suggesting a protective role of p58IPKin the retina. However, the mechanisms remain elusive. Herein, we investigated the cellular mechanisms underlying the neuroprotection action of p58IPKusing conditional knockout (cKO) mouse lines where p58IPKis deleted in retinal neurons (Chx10-p58IPKcKO) or in myeloid cells (Lyz2-p58IPKcKO). In addition, we overexpressed p58IPKby adeno-associated virus (AAV) in the retina to examine the effect of p58IPKon RGC survival after ocular hypertension (OHT) in wild type (WT) mice. Our results show that overexpression of p58IPKby AAV significantly improved RGC survival after OHT in WT mice, suggesting a protective effect of p58IPKon reducing RGC injury. Conditional knockout of p58IPKin retinal neurons or in myeloid cells did not alter retinal structure or cellular composition. However, a significant reduction in the b wave of light-adapted electroretinogram (ERG) was observed in Chx10-p58IPKcKO mice. Deletion of p58IPKin retinal neurons exacerbates RGC loss at 14 days after OHT. In contrast, deficiency of p58IPKin myeloid cells increased the microglia/macrophage activation but had no effect on RGC loss. We conclude that deletion of p58IPKin macrophages increases their activation, but does not influence RGC survival. These results suggest that the neuroprotective action of p58IPKis mediated by its expression in retinal neurons, but not in macrophages. Therefore, targeting p58IPKspecifically in retinal neurons is a promising approach for the treatment of neurodegenerative retinal diseases including glaucoma.