NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the availability of NAD in several tissues can become limited during genotoxic or metabolic stress and over the course of natural aging. We examined the metabolic consequences of specifically depleting Nampt, an essential enzyme in the NAD salvage pathway in muscle. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance. Administration of the NAD precursor nicotinamide riboside rapidly ameliorated functional deficits and restored muscle mass despite having only a modest effect on the intramuscular NAD pool. The limited effectiveness of orally delivered NR appears to be due to metabolism in the liver, as intravenous administration fully rescued intramuscular NAD levels. We employ tracer studies to compare the effectiveness of supplementing with NR vs NMN to increase intramuscular NAD, and to establish that intact nucleotides contribute to the mitochondrial NAD pool. Finally, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function.