Clostridioides difficile infection (CDI) is recognised as the leading cause of nosocomial-associated, infectious diarrhoea globally. The toxin-mediated damage caused during CDI is primarily observed in the colon, with significant injury sustained to the intercellular junctions, polarity determinants and stem cell niches of the colonic epithelial lining. The effects elicited by CDI and its toxins, TcdA and TcdB, during acute infection have been well-reported. However, their impact on colonic homeostasis and regeneration, and the subsequent effects on the incidence and severity of CDI relapse, systemic, and extraintestinal complications, is less well explored. Here we report, via the use of a novel CDI recovery mouse model, that CDI induces severe and substantial damage to the integrity of the colonic lining that takes up to 23 days post-infection to repair, compared to the normal lining turnover rate of 2-3 days. This repair occurs in a wave-like pattern and appears to be correlated with CDI-mediated subversion of homeostatic colonic stem cells and their regenerative capacity, alongside the activation of damage-induced backup repair mechanisms. Furthermore, we observed the improperly repaired, prolonged leaky gut induced by CDI can trigger inflammation and systemic complications in extraintestinal organs as far as the thymus. However, these effects appear to resolve within a few days of infection. Our findings indicate a novel mechanism by which enteric pathogens may impede the repair process of the host to increase the severity of illness and propagate disease. Such findings provide insight into the impact of enteric infections at and beyond the site of local damage as well as the effectiveness and appropriateness of current treatments, providing foundations for novel investigations into new therapies and preventative measures to enhance recovery and circumvent the reliance on antibiotics.