With 1.6 million deaths in 2021, tuberculosis (TB) is one of the top 10 causes of death worldwide. Despite concerted international efforts, this disease remains a global health crisis. Mycobacterium tuberculosis (Mtb), the bacterium responsible for TB, can disseminate throughout the human body resulting in harder to treat and more severe disease. Alarmingly, cases of disseminated TB are increasing globally yet the mechanisms by which this occurs are poorly understood. Here we demonstrate that Mtb interacts with plasminogen, exclusively with human type-II (hPlg). We constructed a unique hPlg expressing transgenic mouse line (C57-hPlg) using CRISPR/Cas9 technology and demonstrated a marked increase in disease severity as measured by bacterial dissemination. Furthermore, we have identified the secreted Mtb protein, Ag85B as the principle hPlg binding ligand, with Lys129 of Ag85B being essential to the interaction at a 1:1 stochiometric ratio. In the C57-hPlg mouse, Ag85B-hPlg interaction results in enhanced Mtb dissemination and a lung pathology which more closely represents human disease. Significantly this includes increased alveolitis, the appearance of foamy macrophages and necrosis in the lungs. Utilising Matrigel, an extra cellular matrix (ECM) surrogate, we have demonstrated that Mtb utilises hPlg to degrade ECM and facilitate bacterial invasion. While Mtb is unable to activate plasminogen directly, Ag85B-hPlg interaction significantly enhances the activity of host-plasminogen activators. We have therefore identified a key host-pathogen interaction not previously appreciated, and revealed a significant moonlighting role for Ag85B during Mtb infection.