INTRODUCTION: Ulcerative colitis (UC) is the most common form of inflammatory bowel disease worldwide. It is a chronic, debilitating condition that affects an individual throughout life. Patients of UC tend to have a reduced quality of life from continuous disease activity and significant complications, with a risk of developing colon cancer later in life. The current therapy does not aim to cure the disease but focuses on suppressing symptoms and improving quality of life. Despite great advances in the modern management of UC with the introduction of new effective drugs, adoption of stricter endpoints, and use of better treatment strategies, there remain many unmet needs. S-Adenosyl-L-methionine (SAMe) is available as a dietary supplement that exerts anti-inflammatory and antioxidant effects. It is also approved for add-on use in depression, osteoarthritis, and liver diseases. The present study examined the gastroprotective effects of SAMe in an animal model that simulates UC. MATERIALS AND METHODS: The aim of this study was to investigate the protective effects of SAMe in an animal model of chronic colitis. After Institutional Animal Ethics Committee (IAEC) approval (IAEC/03/2022), 32 Swiss albino mice were divided into four groups with eight animals per group as the normal control (NC), disease control (DC), positive control (SLZ), and test group (SAMe). All study groups except the NC group (given normal saline) were administered 2% dextran sulfate sodium (DSS) in drinking water for seven days and only drinking water for the next seven days. This cycle of 14 days was repeated three times to induce chronic colitis. The positive control group was given sulfasalazine 100 mg/kg/day, and the test group was given SAMe 200 mg/kg/day from day 1 to day 42. The Disease Activity Index (DAI) was assessed every seven days. On day 42, all animals were sacrificed, and the colon was isolated to assess the weight-by-length ratio, macroscopic grading, histopathological scoring, and biomarkers: TNF-alpha and glutathione (GSH). The colon weight-by-length ratio was assessed and analyzed using one-way ANOVA. DAI, colitis macroscopy, and histopathology score were assessed and analyzed using the Kruskal-Wallis test. A value of p < 0.05 was considered to be statistically significant. RESULTS: It was observed that SAMe significantly reduced the colon weight-by-length ratio, colitis macroscopy grading, DAI, histopathology score, and TNF-alpha level as compared to the DC group, which indicated its anti-inflammatory effect. SAMe also significantly increased the GSH level as compared to the DC group, which indicated its antioxidant effect. Also, it was observed that the effects of SAMe were comparable to the positive control sulfasalazine. CONCLUSION: According to our study's findings, SAMe exerts a gastroprotective effect comparable to that of sulfasalazine, as evidenced by the reduction in DAI, colon weight-by-length ratio, macroscopy grading, histopathology score, and TNF-alpha level. The increase in the GSH levels by SAMe signifies a decrease in oxidative stress, which may be responsible for the gastroprotective effect.