Atherosclerosis is a potentially life-threatening cardiovascular disease characterized by chronic endothelial inflammation and the formation of atherosclerotic lesions. Circulating ox-LDL is known to induce atherosclerosis by triggering oxidative stress, the expression of inflammatory mediators and adhesion molecules, as well as downregulating the atheroprotective transcriptional factor KLF2. Aloperine is an alkaloid compound isolated from the plant Sophora alopecuroides. Here, we employed various experimental methods to determine the effects of aloperine on ox-LDL-induced markers of atherosclerosis. DHE staining revealed that aloperine may restore the oxidant/antioxidant balance in HUVECs by reducing the level of ROS and rescuing the reduction in NOQ-1 and GCLC induced by ox-LDL. Aloperine treatment reduced ox-LDL-induced expression of IL-6, MCP-1, VCAM-1, and E-selectin and rescued the reduction in KLF2. Aloperine also downregulated ox-LDL-induced expression of the LOX-1. We also demonstrate that aloperine improved cell viability and inhibited the adhesion of U937 monocytes to HUVECs. Finally, we demonstrate that the effects of aloperine are mediated through the rescue of KLF2 expression via suppression of the phosphorylation of p53 protein. Together, our results implicate the potential of aloperine as a safe and effective antiatherosclerosis treatment. © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.