Castration-resistant prostate cancer (CRPC) refers to a population of prostate cancer patients who are no longer responsive to androgen deprivation therapy (ADT). Metastatic CRPC is currently lethal, underscoring the urgent need to identify novel therapeutical targets to reverse disease outcome. Unresponsiveness to ADT is multifactorial and often associated with prostate cancer cell’s plasticity, leading to the arise of several CRPC subtypes, which should be individually address for the identification of targetable vulnerabilities. Particularly, the development of mesenchymal stem-like phenotypes is associated with CRPC. The Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway, whose deregulation is associated with CRPC. Here we showed that YAP depletion in mesenchymal stem-cell like PC cells leads to the downregulation of proteins previously associated with epithelial to mesenchymal transdifferentiation (EMT), including N-methylnicotinamide transferase (NNMT). NNMT is also involved in cellular energetics, by competing with nicotinamide phosphoribosyltransferase (NAMPT) for nicotinamide. Thus, we found that mesenchymal-like prostate cancer cells with upregulation of NAMPT, but not epithelial ones, are sensitive to NAMPT inhibition (FK866). NNMT depletion counteracts FK866 toxicity by maintaining cellular nicotinamide levels. Moreover, we identified NNMT as a marker of a subtype of CRPC with stem-cell properties (CRPC-SCL) in which YAP is a main targetable vulnerability. Transcriptomics analysis of a murine-derived prostate cancer cell line exposed to stem cell conditions (DVL3-SCM), unraveled a strong upregulation of NNMT transcripts, in comparison to the parental counterpart (DVL3-PAR). DVL3-SCM presented an increased mesenchymal phenotype and aggressiveness in vitro. In conclusion, we found a specific vulnerability of a subpopulation of CRPC showing that NAMPT inhibition can be an effective molecular targeting strategy to overcome therapy resistant metastatic PC cells with mesenchymal, YAP dependent, phenotype. Notably, the efficacy of NAMPT targeting is potentiated by its dependency on YAP NNMT expression.