Medical-grade polymers have revolutionized the medical device industry but have also introduced significant concerns, particularly regarding infection risks. Infections at surgical sites and on implantable devices such as catheters, stents, and cannulas occur in 4% of patients every day, with over 10% of these cases resulting in death. These infections impose a considerable economic burden on healthcare systems and patients, hindering progress toward effective solutions. Current reliance on antibiotics is increasingly ineffective due to the rise of drug-resistant bacteria, with only four novel antibiotics in development targeting critical pathogens, and only one expected to reach the market. Consequently, new antimicrobial technologies with low resistance potential and proven efficacy are urgently needed. Nitric oxide (NO), an endogenous, short-lived gas produced by nitric oxide synthase enzyme, has demonstrated anti-inflammatory, antimicrobial, antithrombotic, and vasodilatory properties. Synthetic NO donors have been developed to replicate these effects; however, challenges remain, including controllable release, material stability, biocompatibility, surface fouling, and tunability. This dissertation explores combinatorial strategies to address these limitations, focusing on enhancing antimicrobial efficacy and precisely tuning NO release to combat critical pathogens effectively. These methods offer significant potential to improve patient’s lives and the medical industry, through enhanced antimicrobial and biocompatibility effectiveness of biomedical devices.