The cell nucleus is an active site of metabolism. Multiple metabolic enzymes that classically function in cytosolic or mitochondrial pathways have been documented within cell nuclei, where they participate in gene regulation, DNA replication, and DNA repair. However, 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, yet the biological significance of its nuclear-cytosolic distribution is incompletely understood. Here, we leveraged cell lines in which ACLY is localized 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 compartment-localized ACLY enables fine-tuning of both processes. Nuclear ACLY preserves histone H3K23 acetylation under glucose limitation and modulates specific transcriptional programs, including suppression of fatty acid and cholesterol synthesis genes. Conversely, cytosolic ACLY most efficiently supports fatty acid synthesis, elongation, and membrane lipid biosynthetic fluxes, reflecting local substrate production and high FASN expression. The data indicate that metabolites such as acetyl-CoA can diffuse between the nucleus and cytosol, but that local synthesis defines a preferential metabolic fate for products, enabling more precise control of cellular processes.