Multiple factors cause atherosclerosis, meaning its pathogenesis is complex, and has not been fully elucidated. Polyunsaturated fatty acids are a member of the fatty acid family, which are critical nutrients for mammalian growth and development. The types of polyunsaturated fatty acids ingested, their serum levels, and fatty acid desaturase can influence the atherosclerotic disease progression. The fatty acid desaturase gene cluster can regulate fatty acid desaturase activity and further affect atherosclerosis. This study reviewed the research progress on the effects of polyunsaturated fatty acids on atherosclerosis regulated by fatty acid desaturase and the relationship between genetic variants of the fatty acid desaturase gene cluster and atherosclerotic cardiovascular disease.