Grape pomace (GP) is rich in polymeric polyphenolics and glycosides which have lower bioefficacy than monomeric and aglycone counterparts. The aim of this study was to determine whether tannin acyl hydrolase [tannase (TNS)] can improve the antioxidant and anti-inflammatory actions of GP in Caco-2 cells treated with IL-1β. TNS increased quercetin content by 45% and decreased quercetin-3-O-rutinoside by 71% as compared to untreated GP. Further, TNS increased total phenols and DPPH, ORAC, and FRAP values by 39, 57, 215, and 12%, respectively. However, GP and GPTNS at 100 and 200μg/mL (dry extract wt/v) displayed comparable efficacy in the reduction of ROS in Caco-2 cells. After 24h pre-treatment, GPTNS (200μg/mL) decreased IL-1β-induced PGE2 and IL-8 secretion by 107 and 83% respectively, and down-regulated NF-κB activation by 63%. Thus, TNS appears to enhance antioxidant and anti-inflammatory activities of GP polyphenolics and suggests their use as a value-added agroindustrial residue.