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<i>Streptococcus pneumoniae</i> (<i>S. pneumoniae</i>) causes severe pulmonary diseases, leading to high morbidity and mortality. It has been reported that inflammasomes such as NLR family pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2) play an important role in the host defense against <i>S. pneumoniae</i> infection. However, the role of NLRP6 in vivo and in vitro against <i>S. pneumoniae</i> remains unclear. Therefore, we investigated the role of NLRP6 in regulating the <i>S. pneumoniae</i>-induced inflammatory signaling pathway in vitro and the role of NLRP6 in the host defense against <i>S. pneumoniae</i> in vivo by using NLRP6^−/− mice. The results showed that the NLRP6 inflammasome regulated the maturation and secretion of IL-1β, but it did not affect the induction of IL-1β transcription in <i>S. pneumoniae</i>-infected macrophages. Furthermore, the activation of caspase-1, caspase-11, and gasdermin D (GSDMD) as well as the oligomerization of apoptosis-associated speck-like protein (ASC) were also mediated by NLRP6 in <i>S. pneumoniae</i>-infected macrophages. However, the activation of NLRP6 reduced the expression of NF-κB and ERK signaling pathways in <i>S. pneumoniae</i>-infected macrophages. In vivo study showed that NLRP6^−/− mice had a higher survival rate, lower number of bacteria, and milder inflammatory response in the lung compared with wild-type (WT) mice during <i>S. pneumoniae</i> infection, indicating that NLRP6 plays a negative role in the host defense against <i>S. pneumoniae</i>. Furthermore, increased bacterial clearance in NLRP6 deficient mice was modulated by the recruitment of macrophages and neutrophils. Our study provides a new insight on <i>S. pneumoniae</i>-induced activation of NLRP6 and suggests that blocking NLRP6 could be considered as a potential therapeutic strategy to treat <i>S. pneumoniae</i> infection.