AbstractSepsis, whole‐body inflammation caused by the contamination of blood by bacteria and endotoxins, affects millions of patients annually with high mortality rates. A recent promising approach to treat sepsis involves the removal of bacteria and endotoxins using extracorporeal blood‐cleansing devices. However, poor specificity, slow recognition of pathogens, and high costs remain the main limitations. Here, the melanin, a biologically derived pigment, is reported for the rapid binding of bacteria and endotoxins from the contaminated blood . This novel approach utilizes the specific binding between Zn2+‐loaded melanin and bacteria/endotoxins with minimal nonspecific interactions with human blood components. Melanin contains various chemical functional groups that allow reversible chelation of metallic ions such as Zn2+ via redox reactions. Zn2+ enables rapid and specific binding with bacteria/endotoxins due to the strong electrostatic interactions between Zn2+ and phosphate ions. The presence of various zinc‐binding proteins on the bacterial cell membrane further enhances the binding. The well‐known biocompatibility and low cost make melanin an ideal material to interface with human blood. Zn2+‐charged melanin can remove 90% of E. coli and 100% of endotoxin in PBS and human blood. Zn2+‐melanin also demonstrated excellent hemocompatibility shown by protein adsorption, blood coagulation, and hemolysis tests.