Oxymatrine, a quinolizidine alkaloid isolated from the traditional chinese herb Sophora flavescens Aiton, has been demonstrated to exert anti-inflammatory and atherosclerotic effects, but the molecular mechanism has yet to be elucidated. Accumulating evidence indicates an important role of NLR family pyrin domain containing 3 (NLRP3) inf lammasome-mediated pyroptosis in the pathogenesis of atherosclerosis. The present study was undertaken to investigate whether oxymatrine attenuates oxidized low-density lipoprotein (ox-LdL)-induced human umbilical vein endothelial cell (HUVEc) injury, an in vitro cell model of atherosclerosis, by inhibiting NLRP3 inflammasome-mediated pyroptosis, and elucidate the role of the sirtuin (SIRT)1/nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway in this process. cell viability and cytotoxicity were detected by ccK-8 assay and a lactate dehydrogenase (LdH) assay kit. cell apoptosis was detected by flow cytometry. Reactive oxygen species (ROS) generation was detected using a ROS assay kit. The malondialdehyde (MdA) content, mitochondrial membrane potential (MMP) level, superoxide dismutase (SOd), catalase (cAT) and glutathione peroxidase (GSH-Px) activities were determined using commercial kits. The inflammatory cytokines levels were measured by ELISA and protein expression was monitored by western blot analysis. The results revealed that oxymatrine alleviated ox-LdL-induced cytotoxicity and apoptosis. concurrently, oxymatrine inhibited ox-LDL-induced NLRP3 inflammasome-mediated pyroptosis in HUVEcs, as evidenced by the significant decreases in the expression of NLRP3, apoptosis-associated speck-like protein containing a c-terminal caspase recruitment domain (ASc), cleaved caspase-1, interleukin (IL)-1β and IL-18 in HUVECs. In addition, NLRP3 siRNA transfection efficiently suppressed ox-LdL-induced pyroptosis and HUVEc injury. Furthermore, oxymatrine promoted SIRT1/Nrf2 signaling pathway activation in HUVEcs subjected to ox-LdL treatment, and SIRT1 deficiency induced by SIRT1 siRNA transfection abolished the protective effect of oxymatrine against ox-LdL-induced injury. SIRT1 siRNA also mitigated the oxymatrine-induced decreases in ROS generation and MdA content, and the increases in MMP as well as the activities of SOd, cAT and GSH-Px in HUVEcs. Moreover, SIRT1 siRNA transfection blocked the inhibitory effect of oxymatrine on NLRP3 inflammasome-mediated pyroptosis in ox-LdL-treated HUVEcs. collectively, these results indicated that oxymatrine may attenuate ox-LdL-induced HUVEC injury by inhibiting NLRP3 inflammasome-mediated pyroptosis via activating the SIRT1/Nrf2 signaling pathway.