A series of novel trimethylpyrazine-2-carbonyloxy-cinnamic acids and esters were designed, synthesized and evaluated for their inhibitory effect on adenosine diphosphate (ADP)-induced platelet aggregation in vitro and also assayed for their protective effect against hydrogen peroxide (H2O2)-induced oxidative damage on Ea.hy926 cells. The results showed that many compounds exhibited high activity in one or both of the assays, of which, compound F0 10 displayed the highest protective effect on the proliferation of the damaged Ea.hy926 cells (EC50 ¼ 1.7 mM), presenting almost 40 times higher potency than that of lipoic acid, and compound F3 was the most active anti-platelet aggregation agent with IC50 ¼ 9.6 mM, comparable to that of clopidogrel. The structure–activity relationships of these compounds were also discussed.