<p>Β-caryophyllene (BCP) is a plant compound that may exert bioactive effects on intestinal epithelial cell (IEC) function, including metabolism of butyrate, which is important for regulating cellular functions. The goal of this study was to investigate the effects of BCP on butyrate utilization in IEC. Caco-2 cells were grown on hanging, semi-permeable inserts as a model for the intestinal barrier. Treatments, including vehicle control, 40&#xa0;µM BCP, 2&#xa0;mM butyrate, and BUT plus BCP were added to the apical side of the insert and incubated for 24 and 48&#xa0;h. Transepithelial electrical resistance (TEER; ohms/cm²) was recorded to estimate barrier function and supernatant samples were taken from apical and basolateral sides. Butyrate and β-hydroxybutyrate (BHB) concentrations were measured by LC–MS to evaluate utilization of butyrate. Targeted gene expression analysis evaluated molecular modulation of BCP. Results suggested that the addition of BCP plus butyrate increased resistance compared to butyrate alone. The addition of BCP plus butyrate resulted in increased BHB production and greater butyrate disappearance. An upregulation of sodium-glucose transport 1 (<i>SLC5A1</i>), monocarboxylic transporters 1 and 4 (<i>SLC16A1 and SLC16A3),</i> and sodium hydrogen transporter 3 (<i>SLC9A3</i>) expression, and downregulation of 3-hydroxybutyrate dehydrogenase 1 (<i>BDH1)</i> and glucose transporter 2 (<i>SLC2A2</i>) expression were observed. These data indicate that BCP may promote the utilization of butyrate in intestinal epithelial cells and may influence barrier integrity. Overall, the results of this study support further investigation into the therapeutic potential of BCP.</p>