Introduction: Ulcerative colitis is a chronic inflammatory bowel disease. Immunosuppressive drugs and various salicylates improve the disease activity index in individuals with ulcerative colitis. Nonetheless, drug resistance and the side effects of these medications drive researchers toward designing studies to find complementary alternatives. Natural compounds, especially derivatives from medicinal plants, hold a special place as supplements. This study aimed to assess the anti-inflammatory effects of the aqueous extract of Pistacia atlantica gum in an experimental model of ulcerative colitis. Materials and Methods: In this study, 20 male BALB/c mice were assigned to four equal groups. The first group served as the healthy control (negative control), the second group represented untreated colitis (positive control), the third group underwent treatment with the aqueous extract of Pistacia atlantica gum, and the fourth group was treated with mesalazine. Ulcerative colitis was induced in all treatment groups except the negative control by using 100 microliters of 4% acetic acid administered intrarectally. The treatment regimen was initiated on the 10th day of post-ulcerative colitis induction and the manifestation of disease symptoms. A week after the final treatment, the mice were euthanized, and various parameters, including levels of myeloperoxidase, nitric oxide, interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and genes, such as iNOS and COX-2, were evaluated. Results: The results indicated that treatment with the aqueous extract of Pistacia atlantica gum significantly decreased the activity of myeloperoxidase (P<0.01), nitric oxide (P<0.05), splenic cell proliferation (P<0.05), expression, and production of inflammatory cytokines, (P<0.05) for IL-1 ß, (P<0.01) for IL-6, and (P<0.01) for TNF-α compared to the positive control group (untreated colitis). Conclusion: As evidenced by the results of this study, it appears that the aqueous extract of Pistacia atlantica gum possesses desirable anti-inflammatory properties that could potentially reduce the disease activity index and inflammatory parameters in the experimental model of ulcerative colitis. Therefore, following further supplementary experiments, it could potentially serve as a complementary therapeutic agent alongside conventional medications for the treatment of patients suffering from ulcerative colitis.