The global burden of tuberculosis (TB) morbidity and mortality remains immense. A potential new approach to TB therapy is to augment protective host immune responses. We report that the antidiabetic drug metformin (MET) reduces the intracellular growth of Mycobacterium tuberculosis (Mtb) in an AMPK (adenosine monophosphate–activated protein kinase)–dependent manner. MET controls the growth of drug-resistant Mtb strains, increases production of mitochondrial reactive oxygen species, and facilitates phagosome-lysosome fusion. In Mtb-infected mice, use of MET ameliorated lung pathology, reduced chronic inflammation, and enhanced the specific immune response and the efficacy of conventional TB drugs. Moreover, in two separate human cohorts, MET treatment was associated with improved control of Mtb infection and decreased disease severity. Collectively, these data indicate that MET is a promising candidate host-adjunctive therapy for improving the effective treatment of TB.