Indwelling medical devices are plagued by two frequent complications – infection and thrombosis. Antibiotics are the clinical standard for fighting infections but are ineffective due to biofilm formation, dosing tolerances, and resistant bacteria strains. Furthermore, gold-standard antithrombotic drugs like heparin and warfarin inefficiently prevent clot formation. Systemic anticoagulation is a delicate balance. Nitric oxide (NO) is a natural antimicrobial and antithrombotic agent. NO release from macrophages exhibits potent broad-spectrum antibacterial properties to aid in killing pathogenic cells. At low NO doses (pM to μM), bacteria in biofilms are dispersed into their planktonic state. At high concentrations (>1 mM), oxidative reactions produce enough reactive oxygen and nitrogen species for bactericidal effects. NO release from endothelial cells quenches platelet activation to preserve vascular function. Platelet activation and consumption are inhibited at NO flux levels from 0.5 to 4 x10-10 mol cm-2 min-1. NO is a gaseous free radical with a short half-life (< 2 s). Therefore, exogenous NO-donor compounds are necessary for long-term antibacterial and antithrombotic effects.This dissertation aims to harness the therapeutic qualities of NO for improved biocompatibility of indwelling medical devices. Novel hemocompatible and antibacterial NO-releasing technologies are developed, each with a specific clinical target in mind. In Chapter 2, a novel methodology for impregnating the NO-donor molecule S-nitrosoglutathione (GSNO) into medical-grade polymers shows improved hemocompatibility for blood-contacting medical devices. Chapter 3 compares the antibacterial effects of polymers blended with GSNO or another NO-donor molecule, S-nitroso-N-acetylpenicillamine (SNAP), to determine which donor is advantageous for preventing infections on the surface of medical devices. Chapter 4 investigates impregnating SNAP into poly(lactic-co-glycolic acid) sutures to prevent Staphylococci surgical site infections. Chapters 5 and 6 explore a targeted antibacterial approach to prevent multidrug-resistant Staphylococci infections. The zinc metalloenzyme is combined with SNAP in a solution and then immobilized onto a SNAP-blended polymeric delivery platform. In Chapter 7, a NO-releasing antibiotic, SNAPicillin, is tested in an optimized polymicrobial culturing technique to combat real-life Staphylococcus aureus and P. aeruginosa in central venous catheter bloodstream infections. Together, these dissertation chapters demonstrate the ability of NO to reduce infection and thrombosis risks associated with indwelling medical devices.