BACKGROUND: Colon inflammation plays an essential role in the development and progression of colorectal cancer. Emerging evidence from clinical and animal studies indicates that metformin may reduce the risk of colorectal cancer through its anti-inflammatory effects. AIMS: To investigate the efficacy of metformin in reducing the risk of colorectal cancer and the possible pathways and mechanisms. METHODS: The Enterotoxigenic Bacteroides Fragilis (ETBF)/azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model was established and low-dose metformin (125 mg/kg) or high-dose metformin (250 mg/kg) was administered daily by gavage. Colon tumors were counted, and colon tissue was stained with hematoxylin and eosin (HE) and Periodic Acid-Schiff's and Alcian Blue (PAS-AB). Colon Ki67, ZO-1 Muc2, Claudin-1, Occludin, MPO, reactive oxygen species (ROS), E-cadherin, CD206 and Arg-1 expression were detected by immunohistochemistry or immunofluorescence staining. NF-κB pathway-related protein expression was assessed by Western blot. Fecal short-chain fatty acid (SCFA) levels were also examined. RESULTS: Our results showed that low- or high-dose metformin ameliorates colonic mucosal damage, reduces colonic inflammation, and eventually inhibits colorectal tumorigenesis in the ETBF/AOM/DSS mouse model. Our further research found that metformin suppresses the expression of TLR4/MyD88/NFκB/MAPK pathway-related proteins, modulates macrophage M2 polarization and increases SCFA levels in colon contents, which may be the mechanisms by which metformin exerts a protective effect against colon carcinogenesis. CONCLUSION: Metformin inhibited colorectal tumorigenesis by suppressing the TLR4/MyD88/NFκB/MAPK pathway, modulating macrophage M2 polarization and increasing SCFA levels. It holds promise as a potentially effective treatment for colorectal cancer.