The surface of a biomaterial and a biological environment are key factors determining the biocompatibility of the material. Determining biocompatibility of medical implants is a critical step toward approval and clinical application. In this study, the biocompatibility of a covalently attached nanocoating of alginate(Alg)/diazoresin(DR)/heparin(Hep) multilayer has been evaluated by thrombin inactivation, protein adsorption, leukocyte adhesion, cytotoxicity in vitro and subcutaneous implantation in vivo. It was found that the outermost layer of the coating played a key role on anticoagulant activity. No significant difference was seen in albumin adsorption between uncoated and coated one. However, the fibrinogen adsorption on DR/polysaccharides coatings was lower than the uncoated Nitinol. Compared with the uncoated Nitinol surface, DR/polysaccharides multilayer coating presented a drastically reduced adhesion in vitro of polymorphonuclear neutrophil leukocytes (PMN) and peripheral blood mononuclear cells (PBMC). Cell biocompatibility tests indicated that the nanocoating of DR/polysaccharides multilayer did not lead to an increase in the cytotoxicity of the Nitinol and the adherent cells maintained good viability. Subcutaneous implantation in C57BL/6 mice suggested that the coated Nitinol had good tissue biocompatibility. The use of alginate interlayer for heparin immobilization instead of proteins such as albumin, collagen, and gelatin may avoid the risk of contamination with pathogenic agents. Hence, the nanocoating of covalently attached DR/polysaccharide multilayer boosts the biocompatibility of Nitinol biomedical devices.