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Cardiovascular diseases remain the major cause of death worldwide. Atherosclerosis is recognized as the common ground of cardiovascular diseases. Inflammatory cytokines-induced attachment of monocytes to endothelial cells is a significant event in the progression of atherosclerosis. As a highly selective dipeptidyl peptidase (DPP)-4 inhibitor, trelagliptin is used for the treatment of type 2 diabetes mellitus (T2DM). However, whether trelagliptin possesses an inhibitory effect on endothelial dysfunction and monocyte adhesion is unknown. In the current study, we tested the effect of trelagliptin in endothelial cells. We used human aortic endothelial cells (HAECs) exposed to interleukin (IL)-1β to mimic the microenvironment of atherosclerosis. Our results showed that trelagliptin inhibited the expression of pro-inflammatory chemokines including monocyte chemoattractant protein 1 (MCP-1), CXCL-1, and IL-6. Furthermore, trelagliptin suppressed the expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Mechanistically, trelagliptin suppressed the activation of activator protein-1 (AP-1) and NF-κB signaling pathways, which modulate the inflammatory process and monocyte adhesion. Collectively, our results showed that trelagliptin had a powerful inhibitory effect on the attachment of monocytes to endothelial cells, indicating that trelagliptin might have a protective effect on cardiovascular diseases such as atherosclerosis.