Background The mycotoxin deoxynivalenol (DON) is a frequent contaminant of grain and cereal products worldwide. Exposure to DON can cause gastrointestinal inflammation, disturb gut barrier function, and induce gut dysbiosis in vivo under basal conditions, but little is known about the effects of DON ingestion in individuals with pre-existing gastrointestinal disease. Objectives Mice were orally exposed to 10 and 100 μg/kg bw/day of DON, corresponding to 10 to 100-fold human tolerable daily intake concentrations, and to the translation in mice of current human daily intake. The effects of DON exposure were explored under steady-state conditions, and in murine models of enteritis and colorectal cancer (CRC). Results After 8 days of DON exposure, an increase of histomorphological and molecular parameters of epithelial proliferation were observed in normal mice, from the duodenum to the colon. The same exposure in a murine model of indomethacin-induced enteritis led to exacerbation of lesion development and induction of ileal cytokines. DON exposure also worsened the development of colitis-associated CRC in mice as shown by increases in endoscopic and histological colitis scores, tumor grades, and histological hyperplasia. In colon of DON-exposed mice, upstream and downstream ERK signaling genes were upregulated including Mapk1, Mapk3, Map 2k1, Map2k2 core ERK pathway effectors, and Bcl2 and Bcl2l1 antiapoptotic genes. The effects observed in the CRC model were associated with alterations in cecal microbiota taxonomic composition and metabolism of bacterial fucose and rhamnose. Strong Spearman's correlations were revealed between the relative abundance of the changed bacterial genera and CRC-related variables. Discussion Ingestion of DON mycotoxin at concentrations representative of human real-world exposure worsened the development of indomethacin-induced enteritis and colitis-associated CRC in mice. Our results suggest that even at low doses, which are currently tolerated in the human diet, DON could promote the development of intestinal inflammatory diseases and CRC.