Clostridioides difficile is the most common identifiable cause of infectious antibiotic-associated diarrhoea in developed countries, with disease mediated by the action of the two major toxins TcdA and TcdB, and a third toxin, CDT. In severe cases, disease can be fatal, with the patient presenting with severe colonic damage and, less frequently, with systemic disease complications. Systemic disease in animal models has also been described, with thymic disorganisation and apoptosis occurring during severe disease in mice. Here, we examine this disease phenotype and show that a ribotype 027 strain of C. difficile causes toxin-dependent thymic atrophy and disorganisation in mice. Disease damage results in reduced thymic size, disorganisation of the thymic cortex and medulla, as well as a reduction of the CD4+CD8+ thymocyte population and proportional changes in the single positive CD4+ or CD8+ naïve T cell populations. We also showed that thymic atrophy is not restricted to a single strain or genetic background of C. difficile, with strains from different ribotypes able to induce disease and thymic atrophy. This atrophy appeared to be linked to the severity of colonic damage, as thymic atrophy was absent in mice that were infected with strains that did not induce severe colonic damage, suggesting toxin-mediated enteric damage induces the leakage of gut contents, including toxins, into circulation, promoting systemic disease and inflammatory responses. Administration of bezlotoxumab (Zinplava), a monoclonal TcdB therapeutic, rescued mice from systemic disease, preventing thymic atrophy and CD4+CD8+ thymocyte depletion, as well as increasing mouse survival, when compared to treatment with vehicle alone (PBS). As the thymus has such a crucial role in T cell production and immune system development, these findings may have important implications in relapse of C. difficile disease and impaired immunity during C. difficile infection.