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Ulcerative colitis is chronic and recurrent disease of the gastrointestinal tract with uncertain etiology and incomplete treatment options. N-methyl-d-aspartate (NMDA) receptor suppression has shown anti-inflammatory effects in-vitro and in-vivo . The aim of present study was to evaluate the role of dizocilpine (MK-801), a noncompetitive NMDA receptor antagonist, on TNBS (trinitrobenzene sulfonic acid)-induced murine model of colitis. Dizocilpine (0.1, 1 and 5 mg/kg) was given to mice intraperitoneally from 24 h before induction of colitis and daily thereafter for 4 days. Dexamethasone (1 mg/kg) was used as the reference drug. Colitis was induced by intracolonic administration of TNBS/Ethanol (50/50 v/v, 40mg/kg). Animals were sacrificed 5 days after colitis induction and distal colons were examined macroscopically and microscopically. The colonic tissue level of pro-inflammatory cytokines including interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) were assessed by ELISA. Myeloperoxidase (MPO) level was also measured in colon. Dizocilpine, particularly with intermediate dose of 1mg/kg significantly improved animal's weight loss as well as macroscopic and microscopic signs of colitis, reduced colonic levels of IL-1β, IL-6, TNF-α and MPO activity. Hence, dizocilpine has significant protective effects in TNBS-induced colitis and NMDA suppression may be a new and effective therapeutic strategy in ulcerative colitis via decreasing in pro-inflammatory cytokine production.