Intestinal inflammation entails a multifactorial pathophysiology, frequently treated by using anti-inflammatory drugs with severe side effects. At the same time, bioactive compounds present in plant materials and derived residues could contribute to reducing the use of such medications in terms of dosage and treatment length. Thus, the phytochemicals of winery byproducts, mainly represented by (poly)phenols, display significant anti-inflammatory and antioxidant potential. However, the functionality of bioaccessible fractions remains underexplored. This study uncovers the capacity of bioaccessible (poly)phenols of winery byproducts to modulate inflammatory mediators and secondary oxidative stress (OS). After in vitro simulated digestion, bioaccessible (poly)phenols exhibited significant inhibitory capacity of nitric oxide, interleukin (IL)-6, IL-8, and TNF-alpha production and prevented OS, lowering reactive oxygen species (ROS) resulting from disturbed cell metabolism while preserving the molecular machinery of cells, involving glutathione, catalase, superoxide dismutase, and glutathione peroxidase. The results retrieved suggested the relevance of specific profiles for efficiently preventing inflammation.