Abstract: This study aimed to clarify the mechanism and active components of Buyang Huanwu Decoction (BYHWD) in alleviating cerebral ischemia reperfusion injury (CIRI) by inhibiting pyroptosis. The key components and targets of BYHWD for CIRI were identified via network pharmacological analysis, followed by molecular docking performed with Autodock and Pymol software. The effects of BYHWD and its active components were validated in vivo and in vitro. A middle cerebral artery occlusion (MCAO) model was established in mouse to assess neural function alterations in mice under various conditions. Concurrently, an oxygen-glucose deprivation/reperfusion (OGD/R) model was developed utilizing mouse brain tissue astrocytes in vitro. Molecular biology experiments were used to verify the predicted key targets. We have determined that the principal components of BYHWD are baicalein and β-sitosterol. By analyzing genes associated with CIRI pathology alongside those linked to pyroptosis, 20 intersecting genes were identified. In conjunction with molecular docking binding energy assessment, TP53 and TNF emerged as pivotal core targets for subsequent validation. Molecular biology experiments confirmed that BYHWD effectively alleviates injury while reducing the expression level of P53. These findings indicate that the primary bioactive constituents of BYHWD were baicalein and β-sitosterol. In addition, BYHWD may inhibit pyroptosis via TNF and TP53 in protecting CIRI. The experiment has been approved by the Experimental Animal Welfare Ethics Committee of Zhejiang Academy of Traditional Chinese Medicine, approval number (KTSC2020037, KTSC2023030).