Nicotinamide adenine dinucleotide (NAD+) plays vital roles in mitochondrial functions, cellular energy metabolism and calcium homeostasis. In this study, we investigated the effect of NAD+ administration for the treatment of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. EAE, a classical animal model of multiple sclerosis (MS), was induced by subcutaneous injection of myelin oligodendrocyteglycoprotein (MOG). The mice were treated with 250 mg/kg (body weight) NAD+ in PBS administered intraperitoneally once daily. We observed that NAD+ treatment could lessen the severity of EAE. Additionally, NAD+ treatment attenuated pathological injuries of EAE mice. We also found that the AMP-activated protein kinase (AMPK)/silent mating-type information regulation 2 homolog 1(SIRT1) pathway was activated in the NAD+-treated mice and NAD+ treatment suppressed pro-inflammatory T cell responses. Our findings demonstrated that NAD+ could be an effective and promising agent to treat multiple sclerosis and its effects on other autoimmune diseases should be explored.