Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) manipulates cellular processes through the translocation of effector molecules into the host cell cytosol. Using a recently established neonatal S. Typhimurium infection model, we provide functional insights into how Salmonella outer protein B (SopB) suppresses early mucosal tissue inflammation and prolongs host survival. Mechanistically, SopB prevents a disintegrin and metalloprotease 17 (ADAM17) activation, plasma membrane translocation and the release of membrane-bound TNFa from enterocytes and reduces epithelial secretion of IL-18 via mTOR controlled secretory autophagy. This abolishes the early epithelial transcriptional response and reduces immune cell recruitment and programmed cell death-mediated mucosal barrier disruption delaying disease progression. The immunosuppressive effect of SopB is independent of the C-terminally encoded phosphatidylinositol phosphatase and phosphotransferase activity but requires an intact N-terminal domain. Thus, here we demonstrate that SopB suppresses the early, post-transcriptional regulation of epithelial cytokine release in an inositol phosphatase independent manner likely promoting pathogen transmission.