Mycobacterium tuberculosis (Mtb)-infected macrophages aggravated the development of pulmonary tuberculosis, but its detailed molecular mechanisms are still largely unknown. Here, the mouse primary peritoneal macrophages were infected with the attenuated strain of Mtb H37Ra, and we firstly verified that targeting a novel METTL3/N6-Methyladenosine (m6A)/LncRNA MALAT1/miR-125b/TLR4 axis was effective to suppress pyroptotic cell death in the Mtb-infected macrophages. Specifically, through performing Real-Time qPCR and Western Blot analysis, we validated that METTL3, LncRNA MALAT1 and TLR4 were elevated, whereas miR-125b and the anti-oxidant agents (Nrf2 and HO-1) were downregulated in Mtb-infected mouse macrophages. In addition, functional experiments confirmed that both ROS scavenger NAC and METTL3-ablation downregulated NLRP3, GSDMD-C, cleaved Caspase-1 and ASC to restrain pyroptotic cell death and decreased the expression levels of IL-1β, IL-18, IL-6 and TNF-α to restrain inflammatory cytokines expression in Mtb-infected macrophages. Next, METTL3-ablation induced m6A-demethylation and instability in LncRNA MALAT1, and low-expressed LncRNA MALAT1 caused TLR4 downregulation through sponging miR-125b, resulting in the inactivation of NLRP3 inflammasome. Finally, silencing of METTL3-induced protective effects in Mtb-infected macrophages were all abrogated by overexpressing LncRNA MALAT1 and downregulating miR-125b. Thus, we concluded that targeting METTL3-mediated m6A modifications suppressed Mtb-induced pyroptotic cell death in mouse macrophages, and the downstream LncRNA MALAT1/miR-125b/TLR4 axis played critical role in this process.