Trimetazidine (TMZ), an anti-ischemic agent with proposed antioxidant properties, was used in a chronic colitis model in order to evaluate its effectiveness as a therapeutic agent in chronic colitis. Treatment of male Swiss Albino rats with ethanol (50%) and trinitrobenzenesulfonic acid (TNBS) (30 mg/kg) produced colitis as evidenced by histopathologic damage and inflammatory alterations, lipid peroxidation [increased malondialdehyde (MDA) levels], and enhanced neutrophil infiltration [increased myeloperoxidase (MPO) activity] without marked change in glutathione status. Administration of TMZ (5 mg/kg) to TNBS-treated rats failed to affect the TNBS-induced changes in histopathology and MPO activities. Unexpectedly, intrarectal (ir) administration of TMZ significantly elevated colonic MDA levels to a greater extent than TNBS alone. Intraperitoneal (ip) TMZ treatment seemed to increase total glutathione (tGSH), GSH, and GSH/GSSg values. In conclusion, our results demonstrated that (a) ir administration of ethanol and TNBS is an effective way of inducing a chronic colitis model, (b) inflammation and lipid peroxidation augment tissue damage in the chronic colitis model, (c) ip TMZ treatment significantly inhibits MDA production in the chronic colitis model, (d) TMZ treatment is more effective via the ip compared to ir route, and (e) TMZ seems to show its antioxidant effect via preserving the tissue's GSH/GSSG ratios.