Abstract: Taohong Siwu Decoction (THSWD), a traditional Chinese medicinal formulation, has been demonstrated to significantly modulate key signaling pathways implicated in atherosclerosis (AS). This review examines the complex mechanisms through which THSWD influences critical pathways, including nuclear factor kappa-B (NF-κB), phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (AKT), Toll-like receptor 4 (TLR4), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR), that play pivotal roles in AS pathogenesis. By synthesizing experimental evidence and existing literature, the review summarizes how THSWD and its bioactive constituents regulate these signaling cascades to ameliorate AS. Furthermore, it highlights the distinctive therapeutic advantages of traditional Chinese medicine (TCM) compounds in managing chronic diseases driven by multi-target and multifactorial mechanisms. Analyzing disease targets from the perspective of signaling pathways enhances the scientific validation of clinical efficacy for such formulations, thereby offering novel insights for future research.