Neuronal death is a key pathological event in multiple neurological diseases. Increasing evidence has suggested that NAD+ and NADH mediate not only energy metabolism and mitochondrial functions, but also calcium homeostasis, aging, and cell death. This article is written to provide an overview about the information suggesting significant roles of NAD+ and NADH in neuronal death in certain neurological diseases. Our latest studies have suggested that intranasal administration with NAD+ can profoundly decrease ischemic brain damage. These observations suggest that NAD+ administration may be a novel therapeutic strategy for some neurological diseases.