Here we report for the first time that mercaptopyrimidine-templated gold nanoclusters (DAMP-AuNCs) can be used as a novel anticoagulant candidate for the design of antithrombotic drugs. Anticoagulant mechanisms revealed that DAMP-AuNCs significantly inhibited thrombus formation by interacting with fibrinogen. Carrageenan-induced mice tail thrombosis model experiments showed that DAMP-AuNCs had antithrombotic efficacy comparable to heparin in vivo. More importantly, these ultrasmall AuNCs possess excellent blood compatibility and only induce negligible bleeding side effects. Our study is a successful attempt at developing novel antithrombotic agents with high biosafety.