Antiplatelet therapy plays a crucial role in medical treatment for patients with acute coronary syndrome. Since percutaneous coronary interventions increase in number and complication, more patients must be treated with antiplatelet therapy for cardiovascular diseases in which arterial thrombosis plays a key role. Present an-tiplatelet therapy is greatly effective in preventing atherothrombotic complications. However, the increased number of patients remain to experience persistent complica-tions although being correctly treated, because of pharmacokinetics and interactions of drugs, genetic background and increased thrombus formation. Therefore, several massive research efforts have taken to offer new antiplatelet drugs with better defen-sive properties without any bleeding risk. Sesamol, a dietary compound derived from sesame lignans, has free radical scavenging and antioxidant properties. Sesamol is effective for hyperlipidemia, antihypertension and lipid peroxidation due to its anti-oxidant and cytoprotective properties. We found that sesamol has potent antiplatelet activity via activation of cyclic adenosine monophosphate (cAMP)- endothelial nitric oxide synthase (eNOS)/ nitric oxide (NO)-cGMP pathway and inhibition of phospho-lipase C (PLC)γ2, protein kinase C (PKC) -p38 MAPK-thromboxane A2 (TxA2). Our another study also found that this compound inhibits nuclear factor-kappa B (NF-κB) signaling events to exert its antiplatelet activity. In this review, we summarize the sesamol’s antiplatelet effect through NF-κB/MAPK and PLC signaling pathways.