We investigated the effects of an ethanol extract of C. denticulatum (EECD) in a mouse model of glaucoma established by optic nerve crush (ONC), and found that EECD significantly protected against retinal ganglion cell (RGC) death caused by ONC. Furthermore, EECD effectively protected against N-methyl-d-aspartate-induced damage to the rat retinas. In vitro, EECD attenuated transformed retinal ganglion cell (RGC-5) death and significantly blunted the up-regulation of apoptotic proteins and mRNA level induced by 1-buthionine-(S,R)-sulfoximine combined with glutamate, reduced reactive oxygen species production by radical species, and inhibited lipid peroxidation. The major EECD components were found to be chicoric acid and 3,5-dicaffeoylquinic acid (3,5-DCQA) that have shown beneficial effects on retinal degeneration both in vitro and in vivo studies. Thus, EECD could be used as a natural neuroprotective agent for glaucoma, and chicoric acid and 3,5-DCQA as mark compounds for the development of functional food.