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Cancer cellular heterogeneity and therapy resistance arise substantially from metabolic and transcriptional adaptations, but how these are interconnected is poorly understood. Here, we show that, in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest (NC) lineage and glucose metabolism genes. Importantly, we show that acetaldehyde is a metabolite source for acetyl-histone H3 modification in an ALDH1A3-dependent manner, providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish melanoma residual disease model, an ALDH1-high subpopulation emerges following BRAF inhibitor treatment, and targeting these with an ALDH1 suicide inhibitor, nifuroxazide, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that the ALDH1A3-ACSS2 couple directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma. [Display omitted] • ALDH-high metabolic activity controls stem cell transcriptional states • Nuclear ALDH1A3 partners with ACSS2 to promote selective acetyl-histone H3 • Acetaldehyde is an acetyl source for ALDH1A3-dependent histone H3 acetylation • ALDH1A3 is a master regulator and drug target of melanoma heterogeneity Metabolic and transcriptional cellular heterogeneity drives melanoma drug resistance and progression. This study reveals that ALDH1A3-ACSS2 directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with histone H3 acetylation and is associated with TFAP2B -neural crest stem cell and glucose metabolism gene expression. The ALDH1A3 metabolism-stem cell axis represents a potential therapeutic vulnerability in melanoma. [ABSTRACT FROM AUTHOR]