Almost all currently approved anticoagulants interfere with hemostasis and increase the risk of bleeding complications. Thus, there is a critical need for safer anti-thrombotic drugs without bleeding risk. Hirudin has demonstrated potent antithrombotic properties, but is clinically limited due to its high bleeding risk. Hirudin variants such as bivalirudin have been developed to address this issue, yet present a similar proportional risk of bleeding. In this study, several hirudin-like peptides were identified from the salivary gland transcriptome of Poecilobdella manillensis. Guided by the structural design principles of bivalirudin, derivatives of these hirudin-like peptides were synthesized and evaluated for their antithrombotic efficacy and safety in thrombosis and ischemic stroke. Results suggested that derived peptides PM3, PM4, PM6 and PM7 can effectively inhibited the activity of thrombin in vitro. Furthermore, PM4, PM6 and PM7 exhibited robust anticoagulant activity in vivo. Importantly, PM4 and PM7 exhibited significantly lower bleeding risk compared to bivalirudin, as well as comparable efficacy in mitigating intracerebral thrombosis in a transient middle cerebral artery occlusion mouse model, without inducing intracerebral hemorrhage. These findings highlight the therapeutic potential of hirudin-like peptide derivatives as promising candidates for the treatment of thrombosis and ischemic stroke, combining efficacy with an improved safety profile.