Colorectal cancer has a high worldwide incidence. The aim of this study was to determine the effect of yacon flour (YF) on oxidative stress, inflammation, and endotoxemia in rats with induced colorectal cancer (CRC). The Wistar male rats were divided and kept for 8 weeks in four groups: S (basal diet, n = 10), Y (YF flour + basal diet, n = 10), C (CRC-induced control + basal diet, n = 12), CY (CRC-induced animals + YF, n = 12). CRC was induced by intraperitoneal injections of 1,2-dimethylhydrazine (25 mg/kg body weight). Groups Y and CY received 7.5% of the prebiotic FOS from YF. The treatment with YF increased fecal secretory immunoglobulin A levels and decreased lipopolysaccharides, tumor necrosis factor alpha and interleukin-12. However, no effect was observed on the oxidative stress by the total antioxidant capacity of plasma, anion superoxide, and nitric oxide analysis of the animals (p < 0.05). The short-chain fatty acids acetate, propionate, and butyrate showed interactions with NF-κB, TLR4, iNOS, and NADPH oxidase by in silico analysis and had a correlation (by the Person analysis) with CRC markers. The yacon flour treatment reduced the inflammation in rats with induced CRC, and could be a promising food to reduce the damages caused by colorectal cancer.