Numerous people experiencing acute myocardial infarction are also experiencing myocardial ischemia-reperfusion injury (MIRI). Pyroptosis is a core mechanism in MIRI. Tongxinluo (TXL) has a significant protective effect on endothelial cell function. This study utilized network pharmacology to investigate how TXL improves ischemia/reperfusion injury through targeting dysfunction of endothelial cells. Network pharmacology analysis identified 40 key targets through which TXL improves I/R by regulating endothelial dysfunction. We administered TXL (1.5 g/kg/d, oral gavage) to C57BL/6 mice for 7 days before inducing I/R injury, and used 400 μg/ml TXL for in vitro H/R injury in HUVECs. We extensively investigated the effects of TXL on pyroptosis in heart tissue and explored the underlying mechanism through biochemical assays, histopathology, and Western blot analysis. Network pharmacology analysis revealed that TXL targets primarily act on pyroptosis and inflammatory pathways. TXL pretreatment significantly improved cardiac function with increased EF% and decreased LVESV and LVEDV compared to the model group. Myocardial enzymes (CK, CKMB, LDH, cTnI) were markedly reduced by TXL pretreatment. TXL significantly decreased IL-18 and IL-1β levels in serum and reduced neutrophil infiltration in the ischemic area. TXL administration notably downregulated the expression of pyroptosis-related factors (NF-κB, NLRP3, cleaved-Caspase1, GSDMD) in both MIRI mouse model and H/R-treated HUVECs. Molecular docking showed that ginsenoside Rg3, a key TXL component, can directly interact with NLRP3 and GSDMD. TXL has a significant protective effect on endothelial cell function during I/R injury through inhibition of pyroptosis via the NLRP3/Caspase-1/GSDMD signaling pathway, preserving microcirculation barrier integrity.