Mercury enters the human body through the food chain and various ways and exists in blood, kidney and other organs, which will cause great harm. Therefore, it is important to design a safe and effective mercury remover for the removal of blood mercury. In this work, we modified a layer of amino‐rich hyperbranched polyamide nanomaterials (HPN) on the surface of Fe3O4 nanoparticles (Fe/HPN‐NH2 NPs). Among them, tetraethylenepentamine was crosslinked with hyperbranched polyamide by methyl acrylate, which effectively increased the number of amino functional groups in the material. The morphology, structural characteristics and composition of Fe/HPN‐NH2 NPs were characterized. The results of adsorption experiments showed that Fe/HPN‐NH2 NPs had good adsorption ability for inorganic mercury and methylmercury in water. Series of in vitro biocompatibility evaluation tests such as coagulation time tests, erythrocyte morphology observation, blood routine test, complement activation and immune factor test at the molecular level showed that the synthesized Fe/HPN‐NH2 NPs had good biocompatibility. When the initial concentration of lead was 1 ppm and the concentration of adsorbent was 10 mg/mL, the removal efficiency of blood mercury can reach up to 65 % without changing the amount of other commonly existing ions. This blood mercury removal strategy provides the possibility for blood purification.