Abstract: In order to search for coumarin-based anti-platelet aggregation compounds with high efficacy and good druggability, twenty-five 3-acetyl-7-hydroxy-coumarin oxime derivatives (6a-6y) were synthesized via Vilsmeier-Haack reaction, Knoevenagel reaction, Williamson reaction, electrophilic substitution reaction and oximation reaction from resorcinol. Their structures were confirmed by HRMS and ¹H NMR spectra. The anti-platelet aggregation activity of the target compounds was evaluated using Born’s turbidimetric method. The results revealed that most of them could significantly inhibit platelet aggregation induced by adenosine diphosphate (ADP), collagen, arachidonic acid (AA) and thrombin. Among them, the target compounds 6a and 6b not only had strong inhibitory activity on platelet aggregation induced by the four inducers, but also exhibited good water solubility (3.46 mg/mL and 3.85 mg/mL, respectively) and lipid-water partition coefficient (2.56 and 2.85, respectively) and were expected to become a preclinical candidate compound with multi-target action against platelet aggregation.