Background: Atherosclerosis is an extremely predominant condition. The morbidity and mortality of cardiovascular and cerebrovascular ailments caused by atherosclerosis have augmented significantly in recent years. The discovery and research of new drugs are therefore obligatory and will be cooperative in the clinical treatment and management of atherosclerosis. Objective: Curcumol extracted from the traditional Chinese medicine (TCM) E-Zhu (Curcumae Rhizoma), is one of the chief bioactive ingredients of Curcuma oil (a marketed drug in China). Materials and Methods: To classify core targets and discover the main biological mechanisms of curcumol against atherosclerosis, a network pharmacology tactic was commenced for data mining, and biological experiments were engaged for validation. Results: Absorption, metabolism and excretion screening using TCM Systems Pharmacology Database and Analysis Platform server, target forecast using public databases, protein-protein interaction network analysis using the STRING database and Kyoto Encyclopedia of Genes and Genomes pathway analysis were engaged to examine the potential mechanisms of curcumol on atherosclerosis. On the basis of data mining, 10 core targets and related pathways were recognized. Furthermore, the key target signaling pathways, interleukin 6 (IL-6), IL-10, and JAK2/STAT3, were authenticated using biological studies. Conclusion: Curcumol could improve atherosclerosis by reducing the formation of foam cells; the mechanism of action was ascribed to the downregulation of IL-6 expression, upregulation of IL-10 expression and inhibition of the JAK-STAT pathway. Therefore, this study will be a basis for further study of the biological roles of curcumol on atherosclerosis.