NAMPT is an important intracellular metabolic enzyme (iNAMPT) regulating the NAD(+) salvage pathway. However, increased cellular stress (infection, inflammation, hypoxia) promotes the secretion of extracellular NAMPT (eNAMPT), a TLR4 ligand and damage-associated molecular pattern protein (DAMP) that directly drives amplification of innate immune-mediated inflammatory, fibrotic, and neoplastic responses to influence disease severity. We sought to examine the mechanisms underlying pyroptotic eNAMPT release from human monocytic THP-1 cells, evoked by Nigericin, and non-pyroptotic eNAMPT secretion elicited by lipopolysaccharide (LPS). Our data indicate eNAMPT secretion/release requires NLRP3 inflammasome activation with substantial attenuation by either NLRP3 inhibition (MCC-950) or targeted genetic deletion of key inflammasome components, including NLRP3, caspase-1, or gasdermin D (GSDMD). Pyroptosis-associated eNAMPT release involved cleavage of the pore-forming GSDMD protein resulting in plasma membrane rupture (PMR) whereas non-pyroptotic LPS-induced eNAMPT secretion involved neither GSDMD cleavage nor PMR, verified utilizing non-cleavable GSDMD mutant constructs. LPS-induced eNAMPT secretion, however, was highly dependent upon NAMPT ubiquitination catalyzed by a complex containing the NEDD4 E3 ligase, Hsp90 (a selective chaperone), and intact GSDMD verified by enzymatic inhibition or silencing of NEDD4, GSDMD, or Hsp90. NAMPT ubiquitination and secretion involves autophagy activation as super-resolution microscopy analyses demonstrate NAMPT co-localization with autophagosome marker LC3B and eNAMPT secretion was significantly reduced by targeted ATG5 and ATG7 inhibition, critical components of the autophagy E3-like complex. These studies provide key insights into eNAMPT secretion that may accelerate the development of therapeutic strategies that address unmet therapeutic needs in inflammatory, fibrotic and neoplastic disorders.