The potential protective and beneficial effects of Lycopene (LYC) in a rat model of acetic acid-induced ulcerative colitis (UC) were evaluated. Forty male albino rats were divided into five equal groups. Group I: (Control normal) rats received no drugs. Group II: (Early ulcerative colitis): rats received 2 ml (3% v/v) glacial acetic acid intra-colonially at 21thday of experiment and sacrificed 3 days later. Group III:(Early ulcerative colitis + Lycopene protected) rats received Lycopene (10 mg/kg body weight/day, orally) for 21 successive days prior to acetic acid administration. Group IV: (Late ulcerative colitis) rats received acetic acid similar to group II for 3 successive days and sacrificed after 21 days. Group V: (Late ulcerative colitis+ Lycopene treated) rats first administered with acetic acid then after 3 days Lycopene was administered for 21successive days. A significant increase in LMalondialdehyde (L-MDA) with marked decreases in reduced glutathione (GSH) level and Catalase (CAT) activity were observed in colon tissue of UC-induced rats. Additionally, a significant up-regulation of nuclear factor kappa B (NF-κB), caspase-3 and transforming growth factor-β1 (TGF-β1) and down-regulation of Interleukin -10 (IL-10) and Beta cell lymphoma-2 (Bcl-2) gene expression levels were observed in colon of UC induced rats. However, a significant depletion of colon tissue L-MDA and down-regulation of NF-κB, caspase-3 and TGF-β1 in addition to marked increases in GSH concentration and CAT activity and up-regulation of IL-10 and Bcl-2 were observed after LYC treatment. Lycopene has powerful antioxidants, anti-inflammatory and anti-apoptotic effects against ulcerative colitis.