Nicotinamide phosphoribosyltransferase’s (Nampt) association with inflammatory bowel disease (IBD) is unclear. The study was aimed at unraveling Nampt’s clinical and diagnostic relevance. The serum concentration (Luminex-xMAP® technology) was measured in 113 patients with Crohn’s disease (CD), 127 with ulcerative colitis (UC) and 60 non-IBD controls: 40 healthy individuals and 20 with irritable bowel syndrome (IBS). The leukocyte (44 CD/37 UC/19 IBS) and bowel expression (186 samples) was also evaluated (RT-qPCR). All were referred to IBD phenotype, activity, treatment, and inflammatory/nutritional/angiogenic/hypoxia indices. Serum-Nampt and leukocyte-Nampt were positively correlated and were more elevated in active-IBD than in IBS, with leukocyte-Nampt being a fair differential marker. Serum-Nampt in UC positively correlated with its clinical and endoscopic activity as well as with pro-inflammatory cytokines. Serum-Nampt ≤1.54 ng/mL was a good indicator of mucosal healing. The expression of Nampt was up-regulated both in inflamed and quiescent colon and reflected, similarly to leukocyte-Nampt, the clinical activity of IBD. Bowel-Nampt was independently associated with IL1B and hypoxia-inducible factor 1α (HIF1A) expression in inflamed bowel but with FGF2 expression in quiescent bowel. In summary, Nampt’s elevation in IBD at local and systemic levels, and protein and mRNA levels, reflects IBD activity and is associated with inflammation, hypoxia (active) and tissue repair (inactive disease).