Occlusion of blood vessels caused by thrombi is the major pathogenesis of various catastrophic cardiovascular diseases. Thrombi can be prevented or treated by antithrombotic drugs. However, free antithrombotic drugs often have relatively low therapeutic efficacy due to a number of limitations such as short half-life, unexpected bleeding complications, low thrombus targeting capability, and negligible hydrogen peroxide (HO)-scavenging ability. Inspired by the abundance of HO and the active thrombus-targeting property of platelets, a HO-responsive platelet membrane-cloaked argatroban-loaded polymeric nanoparticle (PNP) was developed for thrombus therapy. Poly(vanillyl alcohol-co-oxalate) (PVAX), a HO-degradable polymer, was synthesized to form an argatroban-loaded nanocore, which was further coated with platelet membrane. The PNP can effectively target the blood clots due to the thrombus-homing property of the cloaked platelet membrane, and subsequently exert combined HO-scavenging effect via the HO-degradable nanocarrier polymer and antithrombotic effect via argatroban, the released payload. The PNP effectively scavenged HO and protected cells from HO-induced cellular injury in RAW 264.7 cells and HUVECs. The PNP rapidly targeted the thrombosed vessels and remarkably suppressed thrombus formation, and the levels of HO and inflammatory cytokines in the ferric chloride-induced carotid arterial thrombosis mouse model. Safety assessment indicated good biocompatibility of the PNP. Taken together, the biomimetic PNP offers multiple functionalities including thrombus-targeting, antioxidation, and HO-stimulated antithrombotic action, thereby making it a promising therapeutic nanomedicine for thrombosis diseases.