Glucose-regulated protein 75 (GRP75), a member of the heat-shock protein 70 family, is known to protect cells from stress-induced injury. However, information regarding its distribution and possible function in the retina is limited. In this study, we performed an optic nerve crush (ONC) model in adult rats and found that GRP75 was significantly upregulated in the retina after ONC. Double immunofluorescent staining revealed that GRP75 was localized in the retinal ganglion cells (RGCs). We also examined the expression profile of active caspase3, whose change was correlated with the expression profile of GRP75. In addition, we utilized co-staining of GRP75 and active caspase3 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) to study their correlation in the retina following ONC. Furthermore, the expressions of Bax, cytochrome c (Cytc), p-extracellular-signal-regulated kinases (ERK)1/2, and p-AKT were enhanced in the retina after ONC, and they were parallel with the expression profile of GRP75. Based on our data, we speculated that GRP75 might play an important role in RGCs apoptosis following ONC.