Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, reinforcing the need for safer and more effective antiplatelet therapies. In this work, we designed and synthesized a series of piperazine-derived thioureas under mild conditions and evaluated their antiplatelet potential through in vitro and in silico approaches. Four derivatives (3a, 3g, 3j, and 3p) significantly inhibited arachidonic acid (AA)-induced platelet aggregation in human platelet-rich plasma, achieving levels comparable to aspirin at the same concentration. These compounds showed no anticoagulant effects or hemolytic toxicity, indicating selective action on primary hemostasis and favorable hemocompatibility. ADMET predictions supported their drug-like properties and low toxicity risk. Molecular docking and molecular dynamics simulations revealed stable interactions with key COX-1 residues, while MM-PBSA calculations confirmed favorable binding energies for the most potent derivatives. Our findings revealed that most active piperazine thioureas demonstrated promising potential as novel antiplatelet agents, offering opportunities to improve the quality of life for individuals affected by or at risk of CVDs.