Clomipramine (tricyclic antidepressant), Risperidone (a non-typical antidepressant), and Escitalopram (selective serotonin reuptake inhibitor antidepressant) might be good candidates for investigating the anti-colitis activity. The incidence of depression with ulcerative colitis in patients has led to the use of antidepressants in their treatment. In addition to the antidepressant effect of these drugs, anti-inflammatory effects have also been reported. In this study, 36 rats were used 2 ml of 3% acetic acid solution rectally to show the colitis. Then, Clomipramine (25 mg/kg), Escitalopram (10 mg/kg), Prednisolone (5 mg/kg), Risperidone (2 mg/kg), and normal saline as the control was administered orally for six days. The levels of Tumor Necrosis factor-alpha (TNF-α), Interleukin-6 (IL-6), and myeloperoxidase (MPO) were measured by Enzyme-linked immune sorbent assay (ELISA), and changes in the tissue pathology were investigated. IL-6 level was significantly reduced after the administration of clomipramine and Prednisolone (p=0.025). Risperidone has significantly reduced MPO activity in colonic tissue (P=0.006). We did find no statistical decrease in MPO activity and TNF-α and IL-6 levels after consumption of Escitalopram (p>0.05). Clomipramine showed the best anti-inflammatory effect compared to Escitalopram and Risperidone. Therefore, clomipramine showed the best relieving effect on inflammation of ulcerative colitis in rats.