Traumatic brain injury (TBI) is one of the most devastating injuries experienced by military personnel, as well as the general population, and can result in acute and chronic complications such as cognitive impairments. Since there are currently no effective tools for the treatment of TBI, it is of great importance to determine the mechanisms of neuronal death that characterize this insult. Several studies have indicated that TBI-induced neuronal death arises in part due to excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), which results in nicotinamide adenine dinucleotide (NAD⁺) depletion and subsequent energy failure. In this study, we investigated whether intranasal administration of NAD⁺ could reduce neuronal death after TBI. Rats were subjected to a weight-drop TBI model that induces cortical and hippocampal neuronal death. The intranasal administration of NAD⁺ (20 mg/kg) immediately after TBI protected neurons in CA1, CA3, and dentate gyrus of the hippocampus, but not in the cortex. In addition, delayed microglial activation normally seen after TBI was reduced by NAD⁺ treatment at 7 days after insult. Neuronal superoxide production and PARP-1 accumulation after TBI were not inhibited by NAD⁺ treatment, indicating that reactive oxygen species (ROS) production and PARP-1 activation are events that occur upstream of NAD⁺ depletion. This study suggests that intranasal delivery of NAD⁺ represents a novel, inexpensive, and non-toxic intervention for preventing TBI-induced neuronal death.