Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons. Astrocytes from diverse ALS models induce motor neuron death in co-culture. Enhancing NAD(+) availability, or increasing the expression of the NAD(+)-dependent deacylases SIRT3 and SIRT6, abrogates their neurotoxicity in cell culture models. To determine the effect of increasing NAD(+) availability in ALS mouse models we used two strategies, ablation of a NAD(+)-consuming enzyme (CD38) and supplementation with a bioavailable NAD(+) precursor (nicotinamide riboside, NR). Deletion of CD38 had no effect in the survival of two hSOD1-linked ALS mouse models. On the other hand, NR-supplementation delayed motor neuron degeneration, decreased markers of neuroinflammation in the spinal cord, appeared to modify muscle metabolism and modestly increased the survival of hSOD1 G93A mice. In addition, we found altered expression of enzymes involved in NAD(+) synthesis (NAMPT and NMNAT2) and decreased SIRT6 expression in the spinal cord of ALS patients, suggesting deficits of this neuroprotective pathway in the human pathology. Our data denotes the therapeutic potential of increasing NAD(+) levels in ALS. Moreover, the results indicate that the approach used to enhance NAD(+) levels critically defines the biological outcome in ALS models, suggesting that boosting NAD(+) levels with the use of bioavailable precursors would be the preferred therapeutic strategy for ALS.