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 various animal models of CDI has been described, with thymic and kidney damage sometimes observed but not well characterised. 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+ double positive T cells. These systemic complications coincided with changes to systemic cytokine production, and markers of liver and kidney dysfunction, such as increased serum urea and creatinine, hypoglycaemia and kidney inflammation. 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 an unexpected reduction in disease severity. As the thymus has a crucial role in T cell immunity, and kidney injury can be a risk factor for C. difficile infection, these findings may have important implications in disease relapse during C. difficile infection. The prevention of thymic atrophy, kidney inflammation and reduced systemic response following bezlotoxumab treatment, also provides new insights into the mechanism of action for this therapeutic.