In this study, we examined the effect of a bacteriophage cocktail (tentatively designated as the Foodborne Outbreak Pill (FOP)) on the levels of Listeria monocytogenes in simulated small intestine, large intestine, and Caco-2 model systems. We found that FOP survival during simulated passage of the upper gastrointestinal was dependent on stomach pH, and that FOP robustly inhibited L. monocytogenes levels with effectiveness comparable to antibiotic treatment (ampicillin) under simulated ilium and colon conditions. The FOP did not inhibit the commensal bacteria, whereas ampicillin treatment led to dysbiosis-like conditions. The FOP was also more effective than an antibiotic in protecting Caco-2 cells from adhesion and invasion by L. monocytogenes (5-log reduction vs. 1-log reduction) while not triggering an inflammatory response. Our data suggested that the FOP may provide a robust protection against L. monocytogenes should the bacterium enter the human gastrointestinal tract (e.g., by consumption of contaminated food), without deleterious impact on the commensal bacteria.