Leprosy is an infectious disease that may present different clinical forms depending on host immune response to Mycobacterium leprae. Mannose-binding lectin (MBL) is an acute phase protein associated with the pathophysiology of leprosy. Some studies have shown that there is a correlation between serum levels of MBL and polymorphisms in its gene associated with susceptibility per se and to different clinical forms. The aim of this study was to conduct a systematic review of publications in the literature that studied the association of MBL with leprosy. Databases were searched until December 2020 (PROSPERO: CRD42020158458), and additional searches were conducted scanning the reference lists of the articles. Two independent reviewers assessed the study quality using the Newcastle-Ottawa Quality Assessment Scale. Finally, 10 eligible articles were included in the study. The overall results indicated that both low MBL serum levels and polymorphisms in the structural or promoter region of its gene seem to be associated as protective factors against the development of severe forms. The results suggest that MBL may play a role in the clinical progression of leprosy.