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We reported an increased accumulation of mast cells (MCs) in the lungs of macaques with active pulmonary TB (PTB), compared with those with latent TB infection (LTBI). MCs respond in vitro to\n                    <jats:italic>Mtb<\/jats:italic>\n                    exposure via degranulation and by inducing proinflammatory cytokines. In the current study, we demonstrate an increased production of chymase by MCs in granulomas of humans and macaques with PTB. Single-cell (sc) RNA sequencing analysis revealed distinct MC transcriptional programs between LTBI and PTB, with PTB-associated MCs enriched in interferon gamma, oxidative phosphorylation, and MYC signaling. In a mouse model, MC deficiency led to improved control of\n                    <jats:italic>Mtb<\/jats:italic>\n                    infection that coincided with reduced accumulation of lung myeloid cells and diminished lung inflammation at chronic stages of infection. Airway transfer of MCs into wild-type\n                    <jats:italic>Mtb<\/jats:italic>\n                    -infected mice showed increased neutrophils, decreased recruited macrophages, and elevated\n                    <jats:italic>Mtb<\/jats:italic>\n                    dissemination to the spleen. 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