Mast cells are key drivers of allergic inflammation. We have previously shown that butyrate, a short-chain fatty acid derived from dietary fibers, inhibits human mast cell activation and degranulation. Here, we characterized the mechanisms underlying butyrate-mediated control of mast cell activity. To this end, we assessed the genome-wide impact of butyrate, a histone deacetylase (HDAC) inhibitor, on the epigenomic control of mast cell gene expression by integrating transcriptome and histone acetylation (H3K27Ac) profiles obtained from butyrate-treated primary human mast cells. Butyrate affected a selective set of genes and gene regulatory elements in mast cells. Most prominent was the hypo-acetylation of promoter regions of highly expressed genes and super-enhancers controlling key mast cell identity genes. Perturbation of super-enhancer activity via pharmacological bromodomain inhibition suppressed degranulation of primary human mast cells, evoking a repression of key mast cell identity genes that resembled the inhibitory effects of butyrate. Our data indicate that butyrate inhibits human mast cell activity via a surprisingly selective targeting of super-enhancers to regulate the core mast cell transcriptional program.