Macrophages conversion to foam cells strongly promoted atherosclerosis progression by plaque formation and plaque rupture. Macrophages swallow oxidized-low density lipoprotein (ox-LDL) to promote foam cell formation. Protease-activated receptor 2 (PAR2) has been reported to take part in atherosclerotic development. However, the effects of PAR2 in macrophages were rarely investigated. In this study, human monocyte, THP-1 was induced to macrophages by using phorbol 12-myristate 13-acetate (PMA). Subsequently, an in vitro model was arranged by using ox-LDL to treat the macrophages. The data showed that inhibition of PAR2 reduced ox-LDL-induced foam cell formation, inflammation, and apoptosis. Additionally, ox-LDL increased PAR2 and inhibited Dickkopf-related protein 1 (DKK1) expression, which is a Wnt signaling inhibitor. PAR2 knocked-down decreased DKK1 and enhanced expression of Wnt3a, β-catenin. Meanwhile, DKK1 overexpression reversed the effects of PAR2 on foam cell formation, inflammation, and apoptosis. In summary, PAR2 is essential for the formation of foam cells, inflammation, and apoptosis in macrophages which plays a critical role during atherosclerosis. PAR2 plays roles in macrophages treated with ox-LDL via DKK1/Wnt/β-catenin signaling.