Pyroptosis, a type of programmed cell death illuminated by inflammasomes and active caspases, is implicated in post-stroke inflammation. Our previous study showed that lncRNA taurine upregulated gene 1 (Tug1) sponging miR-145a-5p modulated microglial activation after oxygen-glucose deprivation (OGD). However, the role and mechanism of Tug1 on post-stroke pyroptosis is not fully clear. Photo-thrombosis stroke mice and OGD-treated BV-2 microglia were established respectively. Tug1 knockdown or overexpression was achieved by intraventricular infusion of AAV-shTug1 in vivo, or transfection of siTug1 and pcDNA3.1-Tug1 in vitro. Neurological function and infarction volume were evaluated. Meanwhile, pyroptosis-associated proteins (IL-1β, IL-18, NLRP3, ASC, cleaved-caspase-1, and GSDMD-N), TLR4, and p-p65/p65 as well as Tug1 and miR-145a-5p were detected 24 h after photo-thrombosis or 4 h after OGD by qRT-PCR, western blot, and ELISA. The correlation between Tug1/miR-145a-5p/Tlr4 axis and pyroptosis was explored by dual-luciferase reporter assay and functional gain-and-loss experiments. Photo-thrombosis or OGD caused neural injury and upregulated pyroptosis-associated proteins, Tug1, TLR4, and p-p65 as well as downregulated miR-145a-5p, which was prevented by Tug1 knockdown in vivo and in vitro. Tlr4 gene, putatively binding with miR-145a-5p by bioinformatics analysis, was found to be a direct target of miR-145a-5p with negative interactions. Furthermore, miR-145a-5p inhibitor abolished the inhibitive effects of siTug1 on TLR4 and p-p65 as well as pyroptosis-associated proteins, whereas miR-145a-5p mimics abrogated the enhanced effects of pcDNA3.1-Tug1 on that, suggesting an involvement of Tug1/miR-145a-5p/Tlr4 axis on pyroptosis. Tug1 contributes NLRP3 inflammasome-dependent pyroptosis through miR-145a-5p/Tlr4 axis post-stroke, providing a promising therapeutic strategy against inflammatory injury.