Sirtuins (SIRTs) are NAD(+)-dependent deacetylases that catalyze the hydrolysis of acetyl-lysine residues. They play an important role in many physiological and pathophysiological processes, such as the regulation of lifespan and the prevention of metabolic diseases. In this study, we analyzed the effect of resveratrol on the gene expression levels of SIRT1, SIRT3, SIRT4, PGC1α, and NAMPT, as well as its effect on NAD(+) and NADH levels, in the liver of non stressed or non impaired wild-type zebrafish. Semiquantative RT-PCR assays showed that resveratrol did not change the mRNA levels of SIRT1 and PGC1α but decreased the expression levels of the SIRT3, SIRT4, and NAMPT genes. The decrease in NAMPT mRNA levels was accompanied by an increase in NADH levels, thereby decreasing the NAD(+)/H ratio. Taken together, our results suggest that resveratrol plays a modulatory role in the transcription of the NAMPT, SIRT3, and SIRT4 genes. Zebrafish is an interesting tool that can be used to understand the mechanisms of SIRTs and NAMPT metabolism and to help develop therapeutic compounds. However, further investigations using healthy experimental animals are required to study the modulation of the SIRT and NAMPT genes by resveratrol before it is used as a nutraceutical compound in healthy humans.