The in vitro anti-inflammatory and prebiotic activity and the content and profile of bioaccessible (poly)phenols and catabolites of raw and sous-vide-cooked red cardoon (Cynara cardunculus L. var. altilis DC) were investigated during gastrointestinal (GI) digestion. Raw cardoon after in vitro GI digestion had 0.7% bioaccessible (poly)phenols, which protected against lipopolysaccharide-induced inflammation by counteracting IL-8, IL-6, TNF-alpha, and IL-10 secretions in differentiated Caco-2 cells. Contrarily, GI-digested sous vide cardoon showed higher (poly)phenol bioaccessibility (59.8%) and exerted proinflammatory effects in Caco-2 cells. (Poly)phenols were highly metabolized during the first 8 h of in vitro fermentation, and nine catabolites were produced during 48 h of fermentation. Colonic-fermented raw and sous-vide-cooked cardoon did not show anti-inflammatory activity in HT-29 cells but presented potential prebiotic activity, comparable to the commercial prebiotic FOS, by stimulating health-promoting bacteria such as Bifidobacterium spp. and Lactobacillus/Enterococcus spp. and by increasing the production of total SCFAs, especially acetate.