Qingxin Tongmai Yin (QXTMY), a classic traditional Chinese medicine (TCM) formula widely used for cardiovascular and cerebrovascular diseases, has unclear multitarget mechanisms against atherosclerosis (AS). This study integrated network pharmacology with experimental validation to investigate these mechanisms. Network pharmacology identified 128 bioactive compounds and 135 potential targets of QXTMY, highlighting key anti-AS targets such as TNF, IL6, insulin (INS), IL1B, MMP9, CCL2, and ALB, with the AGE-RAGE signaling pathway as a central mechanism; principal active ingredients included quercetin, kaempferol, luteolin, and cryptotanshinone. In vitro experiments using THP-1-derived macrophages induced with phorbol-12-myristate-13-acetate (PMA) and oxidized low-density lipoprotein (ox-LDL) showed that QXTMY significantly suppressed inflammatory responses, inhibited foam cell formation, and downregulated the AGE-RAGE signaling pathway, as measured by Western blot, ELISA, cholesterol quantification, and Nile Red staining. These findings suggest that QXTMY may exert protective effects against AS, potentially via suppression of the AGE-RAGE-mediated inflammatory axis. However, in vivo validation is still required to support these preliminary conclusions.