Atherosclerosis (As) is a lipid-driven chronic inflammatory vascular disease, the pathogenesis of which primarily includes lipid metabolism disorders and inflammatory responses. Calpain, a calcium-dependent cysteine protease, has been shown to be involved in the development of As. Especially calpain in macrophages plays an important role in regulating lipid metabolism and inflammatory responses in As. This article reviews the possible pathways and molecular mechanisms of macrophages calpain involvement in As trying to provide new ideas for the prevention and treatment of As.