Human tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains a global public health threat. Granulomas constitute a hallmark of TB pathogenesis that can clear, contain, or exacerbate an infection. Containment is exploited by Mtb as a hideout to persist in a dormant, antibiotic-tolerant state, only to resuscitate upon immunosuppression. The immune determinants of a granulomatous response driving Mtb persistence remain elusive. We here generated ex vivo granuloma-like structures from peripheral blood mononuclear cell specimens of TB patients and applied high-dimensional mass cytometry to elucidate immune factors prompting Mtb dormancy. Compared with healthy controls, patient-derived specimens rapidly forced Mtb to become dormant-like ex vivo. This observation correlated with an enrichment in activated, innate (-like) cytotoxic lymphocytes and required the presence of CD56+ lymphocytes or, more specifically, the content of their granules. Finally, we demonstrated that direct exposure to granulysin induces Mtb dormancy, thereby unravelling an immune escape mechanism to cytotoxic lymphocyte activity.