Purpose: Recent epidemiological studies have shown that habitual consumption of extra virgin olive oil (EVOO), the characteristic culinary fat of the Mediterranean area, is effective in the prevention of diverse types of digestive disorders such as inflammatory bowel disease. Many of these benefits are, in addition to its high proportion of oleic acid, due to the high content of phenolic compounds. Methods: Six-week-old mice were randomized into three dietary groups: standard, EVOO and hydroxytyrosol-enriched EVOO. After 30 days, mice that were exposed to 3% DSS for 5 days developed acute colitis that progressed to severe chronic inflammation during a regime of 21 days of water. Results: Diets enriched with EVOO significantly attenuated the clinical and histological signs of damage, improving results from disease activity index and reducing about 50% the mortality caused by DSS. Moreover, hydroxytyrosol supplement showed better results. Cytokines study showed that TNF-α was maintained near to sham control and IL-10 levels were significantly improved in EVOO and EVOO plus hydroxytyrosol diet-DSS groups. In the same way, COX-2 and iNOS were downregulated, and the activation of p38 MAPK was reduced. We also observed a higher significant reduction in iNOS in hydroxytyrosol-enriched EVOO compared with EVOO alone.Conclusions: EVOO diets exerted a noteworthy beneficial effect in chronic DSS-induced colitis by cytokine modulation and COX-2 and iNOS reduction via downregulation of p38 MAPK. In addition to the beneficial effect by EVOO, supplementation of the diet with hydroxytyrosol may improve chronic colitis through iNOS downregulation plus its antioxidant capacity.