The results of this study suggest that elevated c-di-GMP levels decrease the activity of the coordinator of metabolism and virulence, CodY, possibly via lower GTP levels, and that decreased CodY activity suppresses <i>L. monocytogenes</i> virulence by the decreased expression of the PrfA virulence regulon.<b>IMPORTANCE</b><i>Listeria monocytogenes</i> is a pathogen causing listeriosis, a disease responsible for the highest mortality rate among foodborne diseases.