Ulcerative colitis (UC) is an inflammatory bowel disease with indefinite etiology. Currently, immune alterations and their consequences are reported to exist beyond UC development. Herein, the potential coloprotective impact of 6 days-administration of two doses of morin (100, 200 mg/kg) was evaluated and compared to dexamethasone against acetic acid-induced ulcerative colitis with particular concern for the molecular immunomodulatory aspects of the underlying mechanisms. Results showed that morin improved the disease activity index, macroscopic ulcer score and survival rates and attenuated acetic acid-induced oxidative stress and inflammation, as indicated by the significant decrease in MDA, NO, TLR4, NF-kappaB, IL-6, IL-17, and IL-23 and a significant increase in the antioxidant defense markers TAC, SOD, GSH, NRF-2, and HO-1. In addition, morin exhibited a significant decrease in CD3, CD4, and ERK1/2 expression. UC-associated pathological changes were markedly normalized by morin. Thus, morin in a dose related manner, proved its coloprotective effect through alleviation of some adaptive immunity alterations beyond UC with molecular insights on its ability to initiate NRF-2/HO-1 signals, and inhibit CD3/CD4, and TLR4/NF-kappaB/IL-23/IL-17 signals in the context of ERK1/2/IL-6 repression.