Nobiletin is a polymethoxylated flavone isolated from citrus peels which possesses a wide range of beneficial effects. Specifically, nobiletin exerts anti-inflammatory, antibacterial, and antioxidant effects. Recent research showed that nobiletin is able to diminish platelet adhesion and aggregation, indicating this compound as a potential therapeutic drug in thrombosis therapy. However, the exact mechanism of nobiletin action on platelets is unclear. Hence, the main goal of our study was to investigate the molecular mechanism of nobiletin-induced platelet inhibition. We demonstrated that nobiletin blocks induced platelet activation and does not cause platelet apoptosis. Inhibition effect of nobiletin on platelets at least partly is mediated by activation of A(2A) adenosine receptor and consequent AC/cAMP/PKA signaling pathway activation.