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Numerous efforts in basic and clinical studies have explored the potential anti-aging and health-promoting effects of NAD⁺-boosting compounds such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). Despite these extensive efforts, our understanding and characterization of their whole-body pharmacodynamics, impact on NAD⁺ tissue distribution, and mechanism of action in various tissues remain incomplete. In this study, we administered NMN via intraperitoneal injection or oral gavage and conducted a rigorous evaluation of NMN’s pharmacodynamic effects on whole-body NAD⁺ homeostasis in mice. To provide more confident insights into NMN metabolism and NAD⁺ biosynthesis across different tissues and organs, we employed a novel approach using triple-isotopically labeled [¹⁸O-phosphoryl-¹⁸O-carbonyl-¹³C-1-ribosyl] NMN. Our results provide a more comprehensive characterization of the NMN impact on NAD⁺ concentrations and absolute amounts in various tissues and the whole body. We also demonstrate that mice primarily rely on the nicotinamide and NR salvage pathways to generate NAD⁺ from NMN, while the uptake of intact NMN plays a minimal role. Overall, the tissue-specific pharmacodynamic effects of NMN administration through different routes offer novel insights into whole-body NAD⁺ homeostasis, laying a crucial foundation for the development of NMN as a therapeutic supplement in humans.