Retinal ischemia is a common cause of visual impairment and blindness. However, despite the significant advances that have been made in understanding the pathophysiology of retinal ischemia, effective treatments are still lacking. The goal of these studies was to use an in vitro model to identify molecules that could be neuroprotective for retinal ganglion cells exposed to ischemia. Ischemia was induced in the rat retinal ganglion cell line, RGC-5, using iodoacetic acid (IAA). Brief treatment with IAA resulted in RGC-5 cell death within 24 h by a non-apoptotic mechanism. Similar to ischemia in vivo, IAA treatment caused a rapid loss of ATP to approximately 50% of control levels. In contrast, changes in markers of oxidative stress occurred more slowly and included an increase in reactive oxygen species and a decrease in glutathione. Specific flavonoids were able to prevent the cell death caused by IAA treatment. Some of the flavonoids also prevented the loss of ATP as well as the changes in markers of oxidative stress. In contrast, classical antioxidants had only a very modest effect on IAA-induced cell death. These results suggest that specific flavonoids may be useful in preventing ischemia-induced retinal ganglion cell death in vivo.