The adherence of monocytes to endothelial cells plays a causal role in the early development of atherosclerosis and is driven by several inflammatory stimuli, which includes oxidized low-density lipoprotein (ox-LDL). Lunasin, a natural peptide identified in soybean seeds, soy-derived food products, other grains and herbal plants, has been found to exert numerous biological activities, including anti-inflammatory and antioxidant properties. However, little is known regarding the mechanism of action of lunasin in ox-LDL-induced endothelial inflammation. The results of the present study indicate that lunasin significantly ameliorated ox-LDL-induced adhesion of THP-1 monocytes to the surface of human umbilical vein endothelial cells (HUVECs). Lunasin also suppressed expression of the adhesion molecules VCAM-1 and E-selectin, but not ICAM-1. Notably, the inhibitory mechanism of lunasin is associated with its stimulatory effects on expression of the KLF2 transcriptional factor. In addition, lunasin treatment could reverse the effects of ox-LDL on the expression of eNOS and PAI-1, the direct target genes of KLF2. Mechanistically, it was proven that the MEK5/ERK5 pathway mediates the effects of lunasin on KLF2 expression. Taken together, the results of this study suggest that dietary or supplementary intake of lunasin may have a prophylactic or therapeutic capacity in cardiovascular diseases such as atherosclerosis.