Tuberculosis results from Mycobacterium tuberculosis (Mtb) infection. Immune responses controlled by Toll-like receptor 4 (TLR4) are closely associated with the host response to pathogens, including Mtb. NLRP3 inflammasome-mediated pyroptosis forms a significant part of the inflammatory response during Mtb infection, and endoplasmic reticulum stress (ERS) is implicated in the activation of the NLRP3 inflammasome. Here, the function of TLR4 in macrophage pyroptosis induced by infection with the Bacillus Calmette-Guérin (BCG) mycobacterial strain was investigated. It was found that infection with BCG activated TLR4 signaling, induced ERS and subsequent NLRP3 inflammasome activation, leading to pyroptosis in mouse lung tissues. The TLR4 inhibitor TAK 242 inhibited the ERS onset, NLRP3 inflammasome stimulation, and pyroptosis, while the ERS inhibitor TUDCA blocked both inflammasome activation and pyroptosis, and the NLRP3 inhibitor MCC950 specifically inhibited pyroptosis. Furthermore, TAK 242, TUDCA, and MCC950 all exacerbated lung injury caused by BCG infection and promoted BCG survival. Similarly, after in BCG-infected THP-1 macrophages, TLR4 signaling was found to mediate NLRP3 inflammasome activation through ERS, thereby inducing pyroptosis. In summary, BCG infection leads to macrophage pyroptosis via the TLR4/ERS/NLRP3 inflammasome signaling axis, providing new insights for further research into the pathogenesis and treatment of tuberculosis.