Dengue virus (DENV), a mosquito-borne flavivirus, is increasing in prevalence and a major health care burden in tropical regions. Infections range from asymptomatic through to life-threatening haemorrhagic fever or dengue shock syndrome. The severe complications of DENV disease have a rapid onset, at a time when the viremia is decreasing and fever has abated, and critically involve endothelial leak and thrombocytopenia. Gastrointestinal (GI) symptoms are more frequently seen in severe DENV infection, and can include diarrhoea, vomiting, bleeding, and abdominal pain. Bacterial LPS is found to be elevated in patient blood, correlating with disease severity, and GI barrier breakdown has been suggested to contribute to the onset of severe disease. However, there is little to no information about GI tract pathology. We established mouse models of DENV infection that mirror the vascular leak and diarrhoea seen in human disease. We have examined the GI tract during DENV infection of AG129 and IFNAR1 KO mice and find inflammation progressing down the length of the intestine, with intensifying pathology in the large intestine later in infection, including edema and mucus depletion, cytokine and chemokine expression as well as mononuclear cell and neutrophil infiltration. Some mice show GI tract permeability and bacterial penetration into tissues, and inflammatory pathology is reduced with a Toll-like receptor 4 inhibitor. We propose that gut barrier breakdown is a key tipping point leading to the rapid onset of severe disease, at a time when patients are otherwise seeming to recover. Therapies aiming to maintain the integrity of the gut barrier may help prevent severe disease.