Nicotinamide phosphoribosyltransferase (NAMPT) is an important regulator enzyme in the mammalian NAD+ synthesis pathway that catalyzes the condensation of nicotinamide (NAM) with 5-phosphoribosyl-1-pyrophosphate (PRPP) to produce nicotinamide mononucleotide (NMN). Considering NAD+ is involved in many cellular processes like cytokine production, metabolism, and aging, resulting in NAMPT has been regarded as a therapeutically important target for various diseases, particularly cancer. Hence, numerous NAMPT inhibitors have been reported to date. However, the side effect profile of these inhibitors have sparked interest in discovering new molecules. Herein, statistically validated field-based 3D-QSAR models were constructed using chemically diverse amide- and urea-containing NAMPT inhibitors. The contour maps resulting from the best model (R2 = 0.8412, Q2 = 0.8464, Pearson-r = 0.9270) were exploited to get insight into structural properties related to NAMPT inhibition and the outcomes of field-based 3D-QSAR analysis appear that the steric interactions contributed to the activity more than electrostatic, hydrophobic, hydrogen bond acceptor (HBA), hydrogen bond donor (HBD), and aromatic ring fields.