During bacterial infections, Toll-like receptor 4 (TLR4) signals through the MyD88- and TRIF-dependent pathways to promote pro-inflammatory and interferon (IFN) responses, respectively. Bacteria can inhibit the MyD88 pathway, but if the TRIF pathway is also targeted is unclear. We demonstrate that, in addition to MyD88, Yersinia pseudotuberculosis inhibits TRIF signaling through the type III secretion system effector YopJ. Suppression of TRIF signaling occurs during dendritic cell (DC) and macrophage infection and prevents expression of type I IFN and pro-inflammatory cytokines. YopJ-mediated inhibition of TRIF prevents DCs from inducing natural killer (NK) cell production of antibacterial IFNγ. During infection of DCs, YopJ potently inhibits MAPK pathways but does not prevent activation of IKK- or TBK1-dependent pathways. This singular YopJ activity efficiently inhibits TLR4 transcription-inducing activities, thus illustrating a simple means by which pathogens impede innate immunity. Display omitted •The Yersinia effector YopJ blocks TRIF signaling and IFNβ production in DCs•YopJ does not block myddosome formation, NF-κB, or IRF3 activation induced by TLR4•Blocking MAPKs is sufficient to prevent MyD88- and TRIF-dependent gene expression•YopJ interference with TRIF signaling prevents DC-mediated activation of NK cells The mechanisms by which pathogens block TLR4 signaling are unclear. Rosadini et al. demonstrate that Yersinia pseudotuberculosis utilizes the effector YopJ to interfere with MAPK pathways downstream of TRIF and MyD88 in dendritic cells. This singular target of YopJ is sufficient to dismantle the entire TLR4-dependent transcriptional response.