Mice are widely used in science and have played an instrumental role in understanding immune mechanisms, testing cancer therapies, and serving as model systems to better understand physiological processess. Mouse models have also been widely used in infectious disease research including in Clostridioides difficile infection (CDI). Mice display similar disease characteristics to human CDI, including susceptibility to disease, clinical symptoms, and pathology, and thus are an ideal in vivo model to investigate treatments. Here we describe a reliable, reproducible model of CDI that allows researchers to investigate the use of prophylactic oral treatments for CDI in mice. Using this model, we report on treatment efficacy using several parameters as a measure of CDI, including survival, bodyweight, colon length, and colonic histology.