Blood contacting medical devices, such as catheters, stents, vascular grafts, and extracorporeal artificial organs, are used in thousands of patients every day. Despite decades of research on developing biocompatible materials, infection and thrombus formation continue to be two of the leading complications with blood contacting medical devices. Thrombus formation can result in significant consequences such as medical device failure, embolism, inaccurate results from sensors, and death; while an estimated 1.7 million healthcare associated infections result in 99,000 deaths per year in the United States alone. The combination of frequent use and the need for higher dosage of antibiotics has led to the development of antibiotic resistant strains of bacteria, further increasing treatment costs and suffering for the patients. A variety of approaches have been used to create materials that can resist protein and bacterial adhesion that leads to infection and thrombosis, including super hydrophilic surfaces, liquid-infused materials, or coating with zwitterionic compounds. However, these materials can be further improved by the addition of active release of bactericidal and antithrombotic agents. Nitric oxide (NO) is naturally produced from healthy endothelium cells, macrophages, and in our sinuses, and is involved in regulating several biological processes such as platelet activation and adhesion, and is a potent broad spectrum antibacterial agent, effective in killing common pathogens associated with hospital acquired infections such as Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Escherichia coli, and Acinetobacter baumanii. Integrating the active release of NO into polymeric materials can provide a biomimetic approach for preventing thrombosis while reducing risks associated with infection. In this dissertation, NO releasing materials are evaluated for their ability to reduce thrombus formation in vivo, and are characterized for several key challenges associated with clinically relevant materials. The efficacy of these materials is then further improved upon by coupling NO releasing materials with novel approaches for creating non-fouling surfaces, for materials that can both passively reduce protein and bacterial adhesion while having bactericidal and antithrombotic properties.