Background and Purpose: Colorectal cancer (CRC) is a major health problem worldwide. Dicarbonyl electrophiles, such as iso-levuglandins (isoLGs), are generated from lipid peroxidation and form covalent adducts with amine-containing macromolecules. We have shown high levels of adducts of isoLGs in colonic epithelial cells from patients with CRC. We thus investigated the role of these reactive aldehydes on colon cancer development. Experimental Approach: We investigated the effect of oral treatment with 2-hydroxybenzylamine (2-HOBA), a natural compound derived from buckwheat seeds that acts as a potent scavenger of electrophiles, on colon carcinogenesis using the azoxymethane-dextran sulfate sodium model of colitis-associated carcinogenesis and mice with epithelial-specific deletion of the adenomatous polyposis coli gene, as a model of sporadic cancer. We also tested 2-HOBA in a murine xenograft of human HCT116 CRC cells implanted into the flank of nude mice. Key Results: 2-HOBA is bioavailable in the colon of mice after supplementation in the drinking water and does affect the colonic microbiome. However, it reduced the level of isoLG adducts to lysine as well as tumorigenesis in both models of CRC. In parallel, we found that NRF2 activation and signaling was decreased in the colon of 2-HOBA-treated mice. Last, the growth of human tumors is significantly attenuated by 2-HOBA supplementation. Conclusion and Implications: 2-HOBA, which has been shown to be safe in humans, reduces colon tumorigenesis and growth of tumor cells in three distinct models of CRC. Thus, 2-HOBA represents a promising natural compound for the prevention and treatment of CRC.