Sodium tanshinone IIA sulfonate (STS) has been reported to protect organ function in sepsis. However, the attenuation of sepsis-associated brain injury and its underlying mechanisms by STS has not been established.C57BL/6 mice were used to establish the cecal ligation perforation (CLP) model, and STS was injected intraperitoneally 30 min before the surgery. The BV2 cells were stimulated by lipopolysaccharide after being pre-treated with STS for 4 h. The STS protective effects against brain injury and in vivo anti-neuroinflammatory effects were investigated using the 48-hour survival rate and body weight changes, brain water content, histopathological staining, immunohistochemistry, ELISA, RT-qPCR, and transmission electron microscopy. The pro-inflammatory cytokines of BV2 cells were detected by ELISA and RT-qPCR. At last, the levels of NOD-like receptor 3 (NLRP3) inflammasome activation and pyroptosis in brain tissues of the CLP model and BV2 cells were detected using western blotting.STS increased the survival rate, decreased brain water content, and improved brain pathological damage in the CLP models. STS increased the expressions of tight junction proteins ZO-1 and Claudin5 while reducing the expressions of tumor necrosis factor α (TNF-α), interleukin-1β(IL-1β), and interleukin-18 (IL-18) in the brain tissues of the CLP models. Meanwhile, STS inhibited microglial activation and M1-type polarization in vitro and in vivo. The NLRP3/caspase-1/ gasdermin D (GSDMD)-mediated pyroptosis was activated in the brain tissues of the CLP models and lipopolysaccharide (LPS)-treated BV2 cells, which was significantly inhibited by STS.The activation of NLRP3/caspase-1/GSDMD-mediated pyroptosis and subsequent secretion of proinflammatory cytokines may be the underlying mechanisms of STS against sepsis-associated brain injury and neuroinflammatory response.Copyright © 2023. Published by Elsevier B.V.