Spore-forming bacteria encompass a diverse range of genera and species, including important human and animal pathogens, and food contaminants. Clostridioides difficile is one such bacterium and is a global health threat because it is the leading cause of antibiotic-associated diarrhoea in hospitals, causing major morbidity and mortality globally. A crucial mediator of C. difficile disease initiation, dissemination and re-infection is the formation of spores that are resistant to current therapeutics, which do not target sporulation. Beyond the initiation of infection, however, the role of spores in the host is poorly understood. In this study we show that the zymogen human plasminogen is recruited to the toxin-damaged gut, resulting in immune dysregulation, tissue degradation and reduced survival. Plasminogen specifically binds C. difficile spores and active plasmin degrades their surface, facilitating rapid germination. We developed and structurally characterized antibodies that inhibit either human plasminogen activation or plasmin activity and tested their therapeutic efficacy. Remarkably, plasminogen activation inhibition reduced disease severity, whereas inhibition of plasmin had no detectable effect. Our data reveal a new disease mechanism in which human plasminogen exacerbates the C. difficile infection cycle and that inhibitors of plasminogen activation may have utility in treating this or other infection-mediated gastrointestinal diseases.