AbstractScope: Garlic is a source of bioactive phytonutrients that may have anti‐inflammatory or immunomodulatory properties. The mechanism(s) underlying the bioactivity of these compounds and their ability to regulate responses to enteric infections remains unclear.Methods and Results: This study investigates if a garlic‐derived preparation (PTSO‐PTS) containing two organosulfur metabolites, propyl‐propane thiosulfonate (PTSO), and propyl‐propane thiosulfinate (PTS), regulate inflammatory responses in murine macrophages and intestinal epithelial cells (IEC) in vitro, as well as in a model of enteric parasite‐induced inflammation. PTSO‐PTS decreases lipopolysaccharide‐induced secretion of TNFα, IL‐6, and IL‐27 in macrophages. RNA‐sequencing demonstrates that PTSO‐PTS strongly suppresses pathways related to immune and inflammatory signaling. PTSO‐PTS induces the expression of a number of genes involved in antioxidant responses in IEC during exposure to antigens from the parasite Trichuris muris. In vivo, PTSO‐PTS does not affect T. muris establishment or intestinal T‐cell responses but significantly alters cecal transcriptomic responses. Notably, a reduction in T. muris‐induced expression of Tnf, Saa2, and Nos2 is observed.Conclusion: Garlic‐derived organosulfur compounds exert anti‐inflammatory effects in macrophages and IEC, and regulate gene expression during intestinal infection. These compounds and related organic molecules may thus hold potential as functional food components to improve gut health in humans and animals.