The absorption of xenobiotics into systemic circulation is impacted by phase II metabolism in the small and large intestine. Enterocytes are absorptive cells in the small intestine that are involved in the metabolism and transport of nutrients and xenobiotics from the lumen to systemic circulation. The inflammatory condition is known to affect endogenous nutrient metabolism and xenobiotic metabolism in the liver. In contrast, minimal attention has been given to the impact of inflammation on the digestion and absorption of dietary compounds. This study examined the influence of an inflammatory environment on the metabolism and distribution of alpha-mangostin in enterocyte-like Caco-2 cells grown on porous membrane inserts. alpha-Mangostin belongs to a family of prenylated polyphenols referred to as xanthones that have antioxidant and anti-inflammatory activities. Xanthones are relatively abundant in the pericarp of mangosteen fruit. Exposure of highly differentiated Caco-2 cells grown to inflammatory cytokines was associated with decreased expression of uridine diphosphate glucuronsyltransferases 1A (UGT1A) and increased beta-glucuronidase activity in Caco-2 cells. Pre-treatment with a pro-inflammatory cocktail altered the metabolism and distribution of alpha-mangostin in three-compartment culture model. The inflammatory state was associated with an increase in the concentration of free alpha-mangostin in Caco-2 cells and the basolateral compartment compared to control cultures. Exposure to pro-inflammatory cytokines also decreased the amount of phase II metabolites (glucuronidated/sulfated) of alpha-mangostin in Caco-2 cells and basolateral medium. This reduction in phase II metabolites of α-mangostin is explained, in part, by reduced expression of UGT1A and increased activity of beta-glucuronidase in Caco-2 cells. Collectively, these findings suggest that inflammation may alter absorption of alpha-mangostin.