Indwelling medical devices have provided significant enhancement to patient’s outcomes, but often come with the risk of infection. Increasing numbers of antibiotic-resistant bacteria have prompted researchers to discover innovative methods to treat and prevent these infections. Nitric oxide (NO) is a free radical produced by endothelial cells, macrophages, and neurons that has demonstrated excellent antimicrobial properties. The incorporation of NO donors within medical grade polymers to mimic endogenous NO release has shown the potential to reduce infection rates and subsequent antibiotic use. Before these materials can move to clinical use some improvements are necessary. Herein, two novel methods of enhancing NO release are described: 1) the addition of a metal ion to catalyze NO release from a S-nitrosothiol donor and 2) covalent attachment of the NO donor directly to the polymer. These modifications allowed for prolonged duration of NO release, increased NO levels, and improved antimicrobial activity.