The C-type lectin member 5A (CLEC5A) is a pattern recognition receptor for members of the Flavivirus family and has critical functions in response to dengue virus and Japanese encephalitis virus. Here we show that CLEC5A is involved in neutrophil extracellular trap (NET) formation and the production of ROS and proinflammatory cytokines in response to L. monocytogenes. Inoculation of Clec5A-/- mice with L. monocytogenes causes rapid bacterial spreading, increased bacterial loads in blood and liver, and severe liver necrosis. In these mice, IL-1b, IL-17A, and TNF expression is inhibited, CCL2 is induced, and large numbers of CD11b+Ly6chiCCR2hiCX3CR1low inflammatory monocytes infiltrate the liver. By day 5 of infection these mice also have fewer IL-17A+ gd T cells, severe liver necrosis and a higher chance of fatality. Thus, CLEC5A has a pivotal function in the activation of multiple aspects of innate immunity against bacterial invasion.