Gut microbiota imbalance and alterations in the chemokine-chemokine receptor interactions are pivotal in the initiation and advancement of ulcerative colitis (UC). The current UC treatments are prolonged, exhibit high recurrence rates, and may lead to colorectal cancer. So, this study explores the efficacy of Helix pomatia (H. pomatia) mucin in preventing DSS-induced UC. This research focuses on investigating the underlying mechanisms, such as oxidative stress, inflammation, and alterations in gut microbiota and chemokine-chemokine receptor interactions, to understand the anti-inflammatory and antioxidant characteristics of the mucin. Using 4 % DSS in drinking water, UC was induced in C57BL/6 mice. For seven days, mice were given oral doses of either H. pomatia mucin or sulfasalazine. The study assessed changes in oxidative stress, gut microbiota, and histopathology, along with expression of IL-6, CXCR4, CCR7, CXCL9, and CXCL10. The H. pomatia mucin exhibited unique contents, including high glycolic acid (200 ± 2.08 mg/L), collagen (88 ± 2.52 mg/L), allantoin (20 ± 2 mg/L), and concentrated vitamins and minerals. Treatment with H. pomatia mucin in high dose demonstrated reduction in DAI, an increase in fecal Firmicutes, and elevated expression of colonic CCR7, CXCL9, and CXCL10, accompanied by enhanced CXCR4 (75 %) and diminished IL-6 (1.33 %) immunostaining. It also alleviated oxidative stress, reduced fecal Bacteroidetes, and mitigated inflammation, indicating its potential efficacy against DSS-induced UC. In conclusion, H. pomatia mucin is a promising candidate that could be an effective adjuvant in the management and prophylaxis of UC. © 2024 The Authors