Inflammation is critical for host defense, but without appropriate control it can cause chronic disease, or even provoke fatal responses. Here we identify a mechanism that limits the inflammatory response. Probing the responses of macrophages to the key sensory Toll-like receptors, we identify that the BTB/POZ, zinc finger transcriptional regulator PLZF limits the expression of inflammatory cytokines products. In accord with this, PLZF-deficient animals express higher levels of potent inflammatory cytokines and mount exaggerated inflammatory responses to infectious stimuli. We show that this protective effect of PLZF is mediated via modulation of macrophage activity. Temporal quantitation of inflammatory gene transcripts shows more rapid gene induction in the absence of PLZF. Genome-wide analysis of histone modifications distinguish that PLZF establishes basal activity states of early response genes to maintain immune homeostasis and limit damaging inflammation. We show that PLZF stabilizes a co-repressor complex that encompasses histone deacetylase activity to control chromatin. Together with our previous demonstration that PLZF promotes the antiviral response, these results suggest a strategy that could realize one of the major goals of immune therapy to retain immune resistance to pathogens while curbing damaging inflammation.