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Microbial infection can trigger the assembly of inflammasomes and promote secretion of cytokines, such as IL-1β and IL-18. It is well-known that <i>Salmonella</i> modulates the activation of NLRC4 (NLR family CARD domain-containing protein 4) and NLRP3 (NLR family pyrin domain-containing 3) inflammasomes, however the mechanisms whereby <i>Salmonella</i> avoids or delays inflammasome activation remain largely unknown. Therefore, we used <i>Salmonella</i> Enteritidis C50336Δ<i>fliC</i> transposon library to screen for genes involved in modulating inflammasomes activation. The screen revealed the galactose metabolism-related gene <i>galE</i> to be essential for inflammasome activation. Here, we found that inflammasome activation was significantly increased in J774A.1 cells or wild-type bone marrow-derived macrophages (BMDMs) during infection by Δ<i>fliC</i>Δ<i>galE</i> compared to cells infected with Δ<i>fliC</i>. Importantly, we found that secretion of IL-1β was Caspase-1-dependent, consistent with canonical NLRP3 inflammasome activation. Furthermore, the virulence of Δ<i>fliC</i>Δ<i>galE</i> was significantly decreased compared to Δ<i>fliC</i> in a mouse model. Finally, RNA-seq analysis showed that multiple signaling pathways related to the inflammasome were subject to regulation by GalE. Taken together, our results suggest that GalE plays an important role in the regulatory network of <i>Salmonella</i> evasion of inflammasome activation.