Long noncoding RNA (lncRNA) MEG3 has been considered as a novel target for alleviating the brain tissue damage during cerebral ischemia-reperfusion injury (CIRI). Numerous studies have reported that pyroptosis is involved in the pathogenesis of CIRI. This study focused on whether MEG3 modulates CIRI via pyroptosis and its underlying mechanism. The middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model and the oxygen glucose deprivation/reoxygenation (OGD/R) cell model were established. si-MEG3 and miR-145-5p inhibitor were transfected to inhibit MEG3 and miR-145-5p, respectively. As a TLR4 inhibitor, Resatorvid inhibits the TLR4 signaling pathway. TTC and TUNEL staining were used for infarction volume and cell death detection. The differential expression of MGE3, miR-145-5p, TLR4, NLRP3, Caspase-1, IL-1β, and IL-18 was determined using real-time PCR and western blot. The interaction between MEG3 and miR-145-5p, as well as between miR-145-5p and TLR4 was confirmed by the dual-luciferase reporter assay. This study confirmed that the elevated expression of MEG3 during CIRI, and it contributes to pyroptosis by regulating miR-145-5p/TLR4 axis. The knockdown of MEG3 reduced the expression of TLR4, NLRP3, Caspase-1, IL-1β, and IL-18, thereby preventing pyroptosis. Inhibition of miR-145-5p reversed the effect of MEG3 knockdown and promoted pyroptosis. Resatorvid, the inhibitor of TLR4, counteracted the effect of miR-145-5p inhibitor and suppressed pyroptosis. Our findings reveal that MEG3 promotes pyroptosis via miR-145-5p/TLR4/NLRP3 axis and aggravates CIRI, suggesting a potential therapeutic target for ischemic stroke.