Grape pomace is rich in polymeric phenolic compounds and glycosides. Enzymatic treatments may change grape pomace’s phenolic composition, producing monomers and aglycones. The aims of this study were to evaluate if tannase-biotransformed grape pomace extracts have improved intestinal anti-inflammatory activity using an in vitro colon model and to analyze significant differences between white grape pomace, and mixed grape pomace varieties, due to the absence of a pomace fermentation process during white wine production. No differences were observed in the cytotoxicity caused by different extracts. All extracts, before and after biotransformation at 100 and 200 μg/mL (dry extract w/v) had comparable efficacy in reducing reactive oxygen species production in Caco-2 cells. After treatment and induction of inflammation using an interleukin 1β (IL-1β) challenge, tannase-treated white grape pomace extract at 200 μg/mL was the most efficient treatment in down-regulating nuclear factor kappa B activation by 40%, compared to control. On the other hand, tannase-treated mixed grape pomace extract significantly decreased prostaglandin E2 production by 81% and interleukin-8 by 61%, being more effective than white grape pomace extract. Overall, both grape pomace extracts after biotransformation were more potent in the amelioration of IL-1β-induced inflammation in Caco-2 cells. White grape pomace extract did not show higher anti-inflammatory activity than mixed grape pomace. In general, the biotransformation improved the anti-inflammatory effect in Caco-2 cells, indicating that the application of a bioprocess in grape residues may contribute to the development of new ingredients and nutraceuticals with anti-inflammatory potential.