Ulcerative colitis (UC), a subcategory of inflammatory bowel diseases, affects more than 2 million people globally. This study sought to investigate the curative ability of aqueous leaf extract of Telfairia occidentalis (ATO) on dextran sodium sulfate (DSS)-mediated colitis in rats. UC was induced by 5% of DSS in drinking water, and the curative ability of ATO was assessed at 200 mg/kg by oral administration for 10 days. The effect of ATO was deduced on anti-inflammatory, preclinical features [disease activity index (DAI)], redox assays, and alterations both microscopic and macroscopic of the colonic mucosa. DSS mediated inflammation in colons of rats with a significant increase in nitric oxide, myeloperoxidase, IL-1β, IL-6, and TNF-α levels compared with a control group. Lipid peroxidation was also induced following exposure of rats to DSS. There is a marked decrease in antioxidant enzymes activities in DSS group. However, treatment with ATO markedly inhibited the colonic inflammation by reversing the elevated levels of inflammatory markers. Furthermore, ATO suppressed the lipid peroxidation chain reaction by reducing the level of malondialdehyde and hydrogen peroxide. ATO attenuates DSS-induced oxidative stress by increase the level of GSH and enhancing the activities of the cytoprotective enzymes (catalase, glutathione-S-transferase, and superoxide dismutase). Taken together, ATO reduced DAI score, inhibited inflammation, suppressed lipid peroxidation, attenuated oxidative stress, and enhanced the antioxidant enzymes activities. These therapeutic effects of ATO might be due to its phytochemicals as showed in gas chromatography-mass spectroscopy results. The findings of this study indicate that aqueous leaf extract of T. occidentalis has could be a drug candidate for the treatment of UC. PRACTICAL APPLICATIONS: The study focused on the curative ability of aqueous leaf extract of Telfairia occidentalis on dextran sodium sulfate (DSS) mediated colitis in rats. The extract elicits beneficial effects against colitis via its ability to reduce mucosal inflammation, suppress lipid peroxidation, attenuate oxidative stress, enhance the antioxidant enzymes activities, and reduce both infiltration of inflammatory cells and mucosal damage in colon. This study provides scientific evidence to the therapeutic ability of aqueous leaf extract of T. occidentalis in the treatment of DSS-induced ulcerative colitis and could be a drug candidate for the treatment of inflammatory bowel diseases in humans.