ABSTRACT Toxoplasma gondii is a widespread zoonotic pathogen of major One Health concern, capable of causing congenital toxoplasmosis in both humans and sheep. Despite its impact, early host–parasite molecular interactions during acute infection in pregnant hosts remain largely unexplored. In this study, we characterized the transcriptomic responses of key tissues involved in early infection (the small intestine, mesenteric lymph nodes, and placenta) in pregnant ewes experimentally infected with T. gondii strain TgShSp1. RNA-seq analysis revealed pronounced, tissue-specific transcriptional changes at 6 days post-infection (dpi), particularly in the mesenteric lymph nodes, characterized by activation of interferon- and cytokine-mediated immune pathways. In contrast, transcriptional responses at 3 dpi were limited, consistent with a silent phase of parasite dissemination. Despite the absence of detectable parasite DNA, placentomes showed modest interferon-associated responses and upregulation of DNA repair and cellular stress pathways. These changes coincided with marked suppression of cell-cycle progression and extracellular matrix remodeling alongside inhibition of angiogenesis and hypoxia pathways. Altogether, early disruption of placental vascular function and tissue remodeling may contribute to fetal loss. In summary, these findings provide new insights into early host responses to T. gondii infection in a pregnant host and identify molecular mechanisms that may predispose to early fetal death during ovine congenital toxoplasmosis. IMPORTANCE Within a One Health framework, T. gondii represents a critical link between human and animal health, as congenital infection can cause reproductive failure, miscarriage, and fetal abnormalities in both humans and livestock. Although the pathogenesis of classical ovine toxoplasmosis is well characterized, abortion occurring during the acute phase of infection without detectable parasite presence in placental or fetal tissues remains poorly understood. This suggests that pregnancy loss may be driven by host-mediated immune and vascular disruptions. Understanding these processes is essential to clarify the pathogenesis of early reproductive failure. By applying transcriptomic approaches to target tissues involved in infection and pregnancy, this study highlights novel molecular pathways and host responses potentially associated with early abortion. Furthermore, as current diagnostic techniques cannot rule out the occurrence of such early events in human congenital toxoplasmosis, this ovine model provides an essential translational tool to explore placental injury and reproductive failure in humans.