Salmonella can appear in the bloodstream within CD18 expressing phagocytes following oral ingestion in as little as 15 minutes. Here, we provide evidence that the process underlying this phenomenon is reverse transmigration. Reverse transmigration is a normal host process in which dendritic cells can reenter the bloodstream by traversing endothelium in the basal to apical direction. We have developed an in vitro reverse transmigration assay in which dendritic cells are given the opportunity to cross endothelial monolayers in the basal to apical direction grown on membranes with small pores, modeling how such cells can penetrate the bloodstream. We demonstrate that exposing dendritic cells to microbial components negatively regulates reverse transmigration. We propose that microbial components normally cause the host to toggle between positively and negatively regulating reverse transmigration, balancing the need to resolve inflammation with inhibiting the spread of microbes. We show that Salmonella in part overcomes this negative regulation of reverse transmigration with the Salmonella pathogenicity island-2 encoded type III secretion system, which increases reverse transmigration by over an order of magnitude. The SPI-2 type III secretion system does this in part, but not entirely by injecting the type III effector SpvC into infected cells. We further demonstrate that SpvC greatly promotes early extra-intestinal dissemination in mice. This result combined with the previous observation that the spv operon is conserved amongst strains of non-typhoidal Salmonella capable of causing bacteremia in humans suggests that this pathway to the bloodstream could be important for understanding human infections.