Preventing coagulation during extracorporeal blood circulation is critical for clinical treatments. Developing anticoagulant materials for key components can reduce reliance on systemic anticoagulants and improve safety. However, such materials often show limited efficacy due to inefficient interactions with pro/anti-coagulation components, resulting from random active site distribution and orientation. Here, efficient, hemocompatible porous anticoagulant materials based on covalent organic frameworks (COFs) are developed for extracorporeal blood circulation. By tailoring their ordered pores (1.4 to 3.2 nm) and functionalities, well-defined binding “pockets” are engineered in COFs, for precise interactions with target coagulant components, realizing anticoagulant mechanisms, including calcium ion adsorption, antithrombin activation, and coagulation factor trapping. These COFs exhibited marked anticoagulation efficacy and hemocompatibility in vitro experiments, as demonstrated by the prolonged activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) by 1.5-2.2, 1.2-2.6, and 1.9-3.6 fold, respectively, in human plasma. Minimal systemic impact is demonstrated in animal experiments, with COFs showing faster recovery of in vivo hemostatic function compared to heparin. Furthermore, the COFs effectively removed blood lipids, achieving 50%, 30%, and 20% removal for TG, TC, and LDL, respectively, in simulated extracorporeal purification, demonstrating dual anticoagulant-detoxification functionality.