Agomelatine is a non-selective melatonin receptor agonist and an atypical antidepressant with anti-inflammatory, neuroprotective, and cardioprotective effects. The renin-angiotensin system modulates blood pressure and vascular homeostasis. Angiotensin II (Ang II) and its receptor Ang II type I receptor (AT1R) are recognized as contributors to the pathogenesis of cardiovascular and cardiometabolic diseases, including diabetes, obesity, and atherosclerosis. The recruitment and attachment of monocytes to the vascular endothelium is a major event in the early stages of atherosclerosis and other cardiovascular diseases. In the present study, we demonstrate that agomelatine reduced Ang II-induced expression of AT1R while significantly inhibiting the attachment of monocytes to endothelial cells induced by Ang II and mediated by ICAM-1 and VCAM-1. Additionally, Ang II inhibited the expression of the chemokines CXCL1, MCP-1, and CCL5, which are critical in the process of immune cell recruitment and invasion. Agomelatine also suppressed the expression of TNF-α, IL-8, and IL-12, which are proinflammatory cytokines that promote endothelial dysfunction and atherogenesis. Importantly, we demonstrate that the inhibitory effect of agomelatine against the expression of adhesion molecules is mediated through the downregulation of Egr-1 signaling. Together, our findings provide evidence of a novel mechanism of agomelatine that may be practicable in the treatment and prevention of cardiovascular diseases.