Background: Therapeutic strategies used for the treatment of irritable bowel syndrome having many limitations due to their side effects; this necessitates searching for new substitutes with similar therapeutic results and limited side effects. In the present study, the anti-inflammatory activity of the mucilage of Colocasia esculenta L. Schott var. typical corm cultivated in Egypt was explored both in vivo and in vitro. Materials and Methods: In vivo anti-inflammatory activity was evaluated based on histopathological examination, determination of ulcer area and ulcer index, and measurement of inflammatory mediators, namely, myeloperoxidase, malondialdehyde, nitric oxide, and tumor necrosis factor-α, in acetic acid-induced ulcerated rat colon, comparing to Prednisolone as a reference drug. In vitro evaluation of the anti-inflammatory activity of the tested mucilage was carried out by measuring its cyclooxygenase (COX-1/COX-2) and 5-lipoxygenase inhibitory activity comparing to Celecoxib and Zileuton as reference drugs, respectively. Results: Pretreatment with the mucilage improved the histopathological features of the rats ulcerated colon and decreased the ulcer area and the ulcer index in a dose-dependent manner. The mucilage improved all the tested inflammatory mediators. In addition, it has a potent COX-2 inhibitory activity with lower effect on COX-1 and 5-lipooxygenase. Conclusion: The obtained results support the use of C. esculenta corm mucilage as an alternative for the treatment of inflammatory bowel disease with minimum gastrointestinal side effects.