Clostridioides difficile infection and diarrhoea is mediated by the action of the two major toxins TcdA and TcdB, and a third, accessory toxin, CDT. In severe infections, following significant colonic epithelial damage, systemic and fatal complications may arise; however, interventions to prevent systemic disease are limited. Systemic disease in animal models has been described, with thymic and kidney damage observable consequences of severe disease in mice. Thus, using a mouse model of C. difficile infection, we examined this systemic disease phenotype. C. difficile infection caused toxin-dependent thymic damage, including reduced thymic size, disorganisation of the thymic cortex and medulla, and depletion of CD4+CD8+ thymocytes. These systemic complications coincided with changes in systemic cytokines, and markers of liver and kidney dysfunction, with increased serum urea and creatinine, and hypoglycaemia and kidney inflammation, detected. Bezlotoxumab, a TcdB-targeted monoclonal therapeutic, was examined as a preventive measure for toxin-mediated systemic disease complications. Although bezlotoxumab did not reduce colonic damage, it successfully prevented systemic disease, preventing thymocyte depletion and kidney inflammation, leading to a significant reduction in disease severity. As the thymus has a crucial role in T cell immunity, these findings may have important implications in understanding disease relapse during C. difficile infection. Additionally, the prevention of thymic atrophy and reduced systemic response following bezlotoxumab treatment also provides new insights into the mechanism of action for this therapeutic.