Intrinsic to Toxoplasma gondii infection is the parasite-induced modulation of the host immune response, which ensures establishment of a chronic life-long infection. This manipulation of the host immune response allows T. gondii to not only dampen the ability of the host to eliminate the parasite, but also to trigger parasite differentiation to the slow growing, encysted bradyzoite form. We previously used RNAseq to profile the transcriptomes of mice and T. gondii during acute and chronic stages of infection. One of the most abundant host transcripts during acute and chronic infection was Z-DNA binding protein 1 (ZBP1). Here, we determined that ZBP1 functions to control T. gondii growth. In activated macrophages isolated from ZBP1 deletion mice (ZBP1-/-), T. gondii has an increased rate of replication and a decreased rate of degradation. We also identified a novel function for ZBP1 as a regulator of nitric oxide (NO) production in activated macrophages, even in the absence of T. gondii infection. Upon stimulation, T. gondii infected ZBP1-/- macrophages display increased pro-inflammatory cytokines compared to wild type macrophages under the same conditions. These in vitro phenotypes recapitulated in vivo with ZBP1-/-mice having increased susceptibility to oral challenge, higher cyst burdens during chronic infection and an elevated inflammatory cytokine response. Taken together, these results highlight a role for ZBP1 in assisting host control of T. gondii infection.