Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality and morbidity worldwide. Chronic inflammation of the endothelium is a pivotal process in the pathogenesis of ASCVD. Therefore, the identification of pro-atherogenic gene expression and subsequent screening out of potential therapeutic agents for vascular inflammation is an attractive issue. The TICAM1 and IRF3 genes were identified as susceptibility genes whose expression was upregulated in lipopolysaccharide (LPS)-induced vascular inflammation. Cilostazol was found to be the most potential bioactive drug for the TICAM1 proteins. Cilostazol pretreatment also increased autophagy and decreased necroptosis and NLRP3/NLRP6 inflammasome formation, as well as the pro-inflammatory cytokine interleukin-1β, in vitro and in vivo. Additionally, cilostazol significantly attenuated the TNF–α–induced elevation in circulating adhesion molecules. Furthermore, cilostazol treatment markedly reduced aortic wall thickening in TNF–α–challenged mice. After experiments into mechanistic understanding, we found that the candidate drug cilostazol reduces vascular inflammation and possibly atherosclerosis progression. Therefore, this study can offer broader evidence of cilostazol for treating individuals with ASCVD or at high risk of ASCVD. Further prospective clinical trials are warranted to confirm its application and effectiveness.