The study investigated the effect of soluble dietary fiber supplementation on gut microbiota, mucosal barrier function, inflammatory markers, and survival in a murine model of sepsis established by cecal ligation and puncture (CLP). The expression of muc2 was down-regulated in septic mice. However, muc2 expression was significantly increased in the septic mice that received soluble dietary fiber. Survival was also improved in the septic mice treated with dietary fiber. The survival benefit was associated with decreased serum concentrations of pro-inflammatory cytokines and reduced neutrophil infiltration in the gut. Furthermore, the mucus thickness, inflammatory response, and degree of gut injury were remarkably alleviated in septic mice treated with soluble dietary fiber, while it was aggravated in septic mice treated with antibiotics in addition to the soluble fiber. Bacterial 16S ribosomal RNA gene sequencing also showed that fiber supplementation caused an increase in the relative abundance of probiotics, commonly associated with metabolic health. Administration of antibiotics to mice fed fiber diet negated the enrichment of probiotics as well as the survival benefit, following cecal ligation and puncture. Dietary supplementation with cellulose offers a microbe-mediated survival advantage in a murine model of sepsis. Improved understanding of the connection between diet, microbiota, and systemic illness may yield new therapeutic strategies for patients with sepsis.