BACKGROUND: Oxidative stress plays a crucial role in the pathogenesis of ulcerative colitis (UC), contributing to mucosal damage and inflammation. Zataria multiflora possesses antioxidant properties, yet clinical evidence regarding its effects in UC remains limited. This study aimed to evaluate the impact of Z. multiflora extract on oxidative stress markers and disease severity in UC patients. METHODS: In this triple-blind, randomized, placebo-controlled trial, 92 patients with mild-to-moderate UC were randomly assigned to receive either Z. multiflora extract (6 mg/kg/day) or a placebo for two months. Oxidative stress markers, including malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD), and thiol groups (SH), were measured before and after treatment. Disease severity was assessed using the Partial Simple Clinical Colitis Activity Index (P-SCCAI). RESULTS: Z. multiflora supplementation significantly increased TAC (p = 0.01), SOD (p = 0.02), and SH (p = 0.01) levels, indicating enhanced antioxidant defenses. However, MDA levels did not significantly decrease (p = 0.06). Clinically, the Z. multiflora group exhibited significant improvements in bowel frequency (p < 0.001), urgency of defecation (p < 0.001), general well-being (p < 0.001), and final P-SCCAI scores (p < 0.001) compared to the placebo group. CONCLUSION: Z. multiflora supplementation improved antioxidant markers and alleviated UC symptoms, though MDA levels remained unchanged. These findings suggest its potential as a complementary therapy for UC. Further large-scale, long-term studies are warranted to confirm its efficacy and optimize dosing.