Atherosclerosis is a chronic inflammatory response caused by activation of endothelial cells, lipid deposition, and other relative pathogenic factor. Omega-3 polyunsaturated fatty acids (n-3 PUFA) play an important protective role in atherosclerosis, however, the underlying mechanism remains unclear. n-3 PUFA could produce different biological active eicosanoid metabolites by cyclooxygenase, lipoxygenase and cytochrome P450 oxidase, alternatively, it competes with arachidonic acid for the common metabolic enzymes to regulate the levels of arachidonic acid-derived eicosanoid metabolites. Based on the metabolic perspective, this paper systematically discusses the atherosclerosis protective mechanism that n-3 PUFA exerts by affecting the eicosanoid metabolism profile.