Early during Gram‐negative sepsis, excessive release of pro‐inflammatory cytokines can cause septic shock that is often followed by a state of immune paralysis characterized by the failure to mount adaptive immunity towards secondary microbial infections. Especially, the early mechanisms responsible for such immune hypo‐responsiveness are unclear. Here, we show that TLR4 is the key immune sensing receptor to initiate paralysis of T‐cell immunity after bacterial sepsis. Downstream of TLR4, signalling through TRIF but not MyD88 impaired the development of specific T‐cell immunity against secondary infections. We identified type I interferon (IFN) released from splenic macrophages as the critical factor causing T‐cell immune paralysis. Early during sepsis, type I IFN acted selectively on dendritic cells (DCs) by impairing antigen presentation and secretion of pro‐inflammatory cytokines. Our results reveal a novel immune regulatory role for type I IFN in the initiation of septic immune paralysis, which is distinct from its well‐known immune stimulatory effects. Moreover, we identify potential molecular targets for therapeutic intervention to overcome impairment of T‐cell immunity after sepsis.