In the present study, a series of novel nitric oxide-hydrogen sulfide releasing derivatives of(S)-3-n-butylphthalide((S)-NBP) were designed, synthesized, and evaluated as potential antiplatelet agents. Compound NOSH-NBP-5 displayed the strongest activity in inhibiting the arachidonic acid(AA)- and adenosine diphosphate(ADP)-induced platelet aggregation in vitro, with 3.8- and 7.0-fold more effectiveness than(S)-NBP, respectively. Furthermore, NOSH-NBP-5 could release moderate levels of NO and H2 S, which would be beneficial in improving cardiovascular and cerebral circulation. Moreover, NOSH-NBP-5 could release(S)-NBP when incubated with rat brain homogenate. In conclusion, these findings may provide new insights into the development of novel antiplatelet agents for the treatment of thrombosis-related ischemic stroke. In the present study, a series of novel nitric oxide-hydrogen sulfide releasing derivatives of (S) -3-n-butylphthalide ((S) -NBP) were designed, synthesized, and evaluated as potential antiplatelet agents. 5 displayed the strongest activity in inhibiting the arachidonic acid (AA) - and adenosine diphosphate (ADP) -induced platelet aggregation in vitro, with 3.8- and 7.0-fold more effectiveness than (S) -NBP, respectively. -5 could release moderate levels of NO and H2 S, which would be beneficial in coronary artery and cerebral circulation. Moreover, NUCT-NBP-5 could release (S) -NBP when incubated with rat brain homogenate. provide new insights into the development of novel antiplatelet agents for the treatment of thrombosis-related ischemic stroke.