<p>Inflammation, oxidative stress and the resulting mitochondrial dysfunction constitute a critical triad in colorectal cancer, whose dynamic interaction reveals valuable avenues for disease management. NAD + /NADH ratio deterioration contributes to the progression of multiple metabolic disorders, including cancer, as it is linked to the above pathological axis. This study investigated the effects of NADH in a 1,2-dimethylhydrazine (DMH)-induced mouse model of colon carcinogenesis, focusing on the hypothesis that NADH mitigates ACF formation and associated inflammatory and oxidative stress responses. The mice were treated with DMH to induce colon cancer and received moderate (50 mg/kg) or high (150 mg/kg) doses of NADH. The key endpoints included aberrant crypt foci (ACF) formation, hematological parameters, and inflammation and oxidative stress markers. DMH treatment resulted in increased ACF formation; and disrupted the colonic histological architecture. Markers of oxidative stress, including malondialdehyde and nitrites, were significantly elevated, whereas antioxidant defenses; such as superoxide dismutase, glutathione peroxidase, catalase, and glutathione, were reduced. Inflammation was evidenced by increased levels of TNF-α and IL-17 while a reduction in IFN-γ levels was noted. NADH administration, particularly at the moderate dose, mitigated these effects by reducing ACF formation (~ 53%), preserving hematological parameters, and restoring the oxidative and inflammatory balance. Additionally, NADH treatment partially improved colonic architecture by reducing dysplasia and maintaining epithelial integrity. These findings demonstrate for the first time that NADH, especially at moderate doses, effectively prevents DMH-induced colon carcinogenesis by preserving immune homeostasis, reducing inflammation, and restoring oxidative balance.</p> Graphical abstract <p></p>