Diabetic neuropathy is a major complication of diabetes mellitus, which is associated with the decrease of cell viability in neuron. Hyperglycemia plays a critical role in the development of diabetic neuropathy. Ginsenosides have been reported to possess anti-diabetic action. However, the effect of ginsenosides in the condition of diabetic neuropathy was not elucidated. Thus, we examined the protective effect of ginseng total saponin (GTS), panaxadiol (PD), and panaxatriol (PT) in the high glucose-induced cell death of PC12 cells, an in vitro cellular model for diabetic neuropathy. In present study, high glucose induced the decrease of cell viability, which was completely prevented by the treatment of GTS, but partially prevented by the treatment of PD and PT. GTS also prevented high glucose-induced increase of lipid peroxide formation and decrease of glutathione (GSH) contents. In addition, GTS, but PD and PT partially, reduced high glucose-induced stimulation of cyclooxygenase-2 (COX-2) expression in PC12 cells. In conclusion, ginsenosides prevented high glucose-induced neuronal cell death via the inhibition of oxidative stress and COX-2 expression in PC12 cells.