Background: Inflammation and oxidative activities within the gut play major roles in the pathogenesis of ulcerative colitis (UC). We aimed to determine the effect of Melissa officinalis, an antioxidant and anti-inflammatory agent, on the colon histological characteristics in acetic acid (AA)-induced UC in rat models. Methods: Thirty-six male rats with AA-induced colitis were divided into 5 groups: no treatment (AA); daily treatment with 300 mg/kg Melissa officinalis orally (MO) and rectally (MR); and 100 mg/kg mesalamine orally (AO) and rectally (AR). Macroscopic and histopathological evaluation of the colon, along with a biochemical laboratory evaluation, were performed 10 days after UC induction. Results: All treatment groups demonstrated lower macroscopic grading scores compared to the AA group. After treatment with MO, 42.9% of cases demonstrated no macroscopic changes, while 14.3% demonstrated only mucosal erythema. In the MR group 28.6% of rats had no changes in their mucosal lining and 28.6% had only mucosal erythema. Following histopathological evaluation, the AO group had lower scores regarding the severity of ulcer, inflammation, destruction, crypt abscess, and disorganization compared to the MO group. (P=0.02) The MR group demonstrated lower microscopic scores compared to the MO group, and also lower macroscopic scores compared to the AR group, although not significantly (P>0.05). Conclusions: Both oral and topical administration of Melissa officinalis have satisfactory healing properties compared to mesalamine, with topical route having better Results:. Therefore, further studies are needed to establish the benefit of Melissa officinalis administration (both orally and topically) within a UC treatment protocol. [ABSTRACT FROM AUTHOR]