Tragopogon graminifolius DC. (Compositae) (TG) has been proposed as an efficacious remedy for gastrointestinal ulcers in Iranian traditional medicine. The present study evaluates the efficacy of TG on experimental colitis and the responsible mechanisms. After induction of IBD by 2,4,6-trinitrobenzenesulfonic acid (TNBS), rats received standardized ethanol extract of TG aerial part at 20, 30, or 50 mg/kg/d orally. After 12 d, the rats were sacrificed and the colon was removed and assessed for macroscopic and microscopic changes. Also, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), total antioxidant capacity, myeloperoxidase (MPO), and lipid peroxidation (LPO) were measured in the colon homogenate. TG extract significantly reduced macroscopic and microscopic scores of colitis with ED50 values of 23 and 39 mg/kg, respectively. MPO was significantly reduced in all plant extract groups with an ED50 value of 41 mg/kg. The ED50 values of extract for inhibition of TNF-α and LPO were 44 and 93 mg/kg, respectively. IL-1β significantly decreased by 50 mg/kg of TG extract (ED50 = 57 mg/kg). Total antioxidant power markedly increased by 50 mg/kg group (ED50 = 43 mg/kg). TG exhibited efficacy on TNBS-induced colitis via anti-inflammatory, immunomodulatory, antioxidant, and mucosal healing properties. TG possesses promising healing function on colitis. Clinical trials are warranted to prove its efficacy and tolerability in IBD.