ABSTRACT Severe dengue virus (DENV) infection can cause hemorrhage and shock, with onset at a time when viremia is decreasing and fever has abated. The factors contributing to the sudden deterioration of patient condition are debated. Gastrointestinal symptoms including vomiting, diarrhea, and abdominal pain are prevalent in severe diseases. The reported correlation of serum lipopolysaccharide levels with disease severity suggests that the gut barrier is compromised. We examined gastrointestinal tract (GIT) pathology in dengue infection, employing AG129 and Ifnar1 −/− mice, as models of primary or antibody-dependent enhancement of infection, respectively. DENV replication peaked early in the spleen, with infected cells appearing later in the GIT, followed by kidney and liver. On day 4 of infection, histological examination showed that DENV-mediated inflammation and tissue damage were severe in the GIT, with non-GIT tissues showing only limited pathology. The inflammatory pathology was found in focal areas, first in the small intestine and later in the proximal and distal colon. The main features included infiltration by neutrophils and monocytes, edema, villus blunting, exfoliation of enterocytes, crypt abscesses, lymphocyte depletion within Peyer’s patches, and mucus discharge from goblet cells. Loss and thinning of the mucus layer resulted in aberrant contact of luminal bacteria with the gut epithelial cells. We hypothesize that DENV-induced gut inflammation compromises the integrity of the gut barrier, subsequently promoting severe dengue disease. IMPORTANCE Dengue virus, an arbovirus, causes an estimated 100 million symptomatic infections annually and is an increasing threat as the mosquito range expands with climate change. Dengue epidemics are a substantial strain on local economies and health infrastructure, and an understanding of what drives severe disease may enable treatments to help reduce hospitalizations. Factors exacerbating dengue disease are debated, but gut-related symptoms are much more frequent in severe than mild cases. Using mouse models of dengue infection, we have shown that inflammation and damage are earlier and more severe in the gut than in other tissues. Additionally, we observed impairment of the gut mucus layer and propose that breakdown of the barrier function exacerbates inflammation and promotes severe dengue disease. This idea is supported by recent data from human patients showing elevated bacteria-derived molecules in dengue patient serum. Therapies aiming to maintain gut integrity may help to abrogate severe dengue disease. Dengue virus, an arbovirus, causes an estimated 100 million symptomatic infections annually and is an increasing threat as the mosquito range expands with climate change. Dengue epidemics are a substantial strain on local economies and health infrastructure, and an understanding of what drives severe disease may enable treatments to help reduce hospitalizations. Factors exacerbating dengue disease are debated, but gut-related symptoms are much more frequent in severe than mild cases. Using mouse models of dengue infection, we have shown that inflammation and damage are earlier and more severe in the gut than in other tissues. Additionally, we observed impairment of the gut mucus layer and propose that breakdown of the barrier function exacerbates inflammation and promotes severe dengue disease. This idea is supported by recent data from human patients showing elevated bacteria-derived molecules in dengue patient serum. Therapies aiming to maintain gut integrity may help to abrogate severe dengue disease.