The cell nucleus has emerged as an active site of metabolism. Multiple metabolic enzymes that classically function in cytosolic or mitochondrial pathways have also been documented within nuclei where they impact gene expression and cell phenotypes. Yet, metabolites can passively diffuse across nuclear pores, and the extent to which the nucleus and cytosol are continuous versus distinct metabolic compartments remains unclear. Both the nucleus and cytosol require acetyl-CoA for specific processes (e.g., histone acetylation and lipid synthesis, respectively), and the acetyl-CoA producing enzyme ATP-citrate lyase (ACLY) is present in both locations. However, the mechanisms governing ACLY’s nuclear localization and the biological significance of its nuclear-cytosolic distribution are incompletely understood. Here, we leveraged cell lines in which ACLY is restricted to either the nucleus or cytosol to investigate its compartmentalized functions. We find that ACLY in either location can support both fatty acid synthesis and histone acetylation, but that compartment-localized ACLY enables fine-tuning of both processes. Nuclear ACLY preserves histone H3K23 acetylation under glucose limitation and regulates specific transcriptional programs including fatty acid and cholesterol synthesis genes, which are suppressed by either WT or nuclear ACLY. Conversely, cytosolic ACLY most efficiently supports fatty acid synthesis and elongation, reflecting both local substrate production and high lipogenesis enzyme levels. The data indicate that acetyl-CoA can diffuse between the nucleus and cytosol, but that local metabolite synthesis enables finer control of cellular processes, suggesting a framework for understanding nuclear metabolism.