Since its identification in 1986 as the endothelium derived relaxing factor, nitric oxide (NO) has gained widespread interest in medicine and physiology, as discovery of an ever-widening range of effects are described and better characterized. Encompassing nearly every physiological system in the body and relevant in myriad pathological processes, nitric oxide, both directly and indirectly, has an enormous influence in the human body. Harnessing the potential of NO in a therapeutic context poses a challenge in that sustained NO delivery, from a pressurized tank or chemical donors, is not a convenient or cost effective approach. What is needed are easily deployed materials that contain either NO or an activatable NO precursor in a stable form that, when applied to the target tissue, releases the generated NO in a controlled and appropriately sustained manner. In the current work, the synthesis of a hybrid material based on sol-gel and glassy matrix components to generate and release NO is presented, along with its applications towards human disease and medical care. The material has been characterized with respect to size, components, and release profiles, and exhibits controlled and sustained NO release. By utilizing the potent antimicrobial effects of NO, the activity of these NO-releasing nanoparticles (NO-np) against many strains of Staphyloccocus aureus is demonstrated in terms of both superficial wounds and infected abscesses. Through histology, immunohistochemistry, electron microscopy, gross measurements, and cytokine analysis, the role of NO supplementation was revealed to have numerous positive effects in these applications. Capitalizing on its critical role in erectile function, NO-np have been applied to an animal model of erectile dysfunction and have shown the ability to initiate and sustain an erection without any measurable side effects. Additionally, NO-np have been used to improve wound healing speed and quality and to modulate systemic blood pressure and hemodynamic factors in animal models. These studies serve to not only reveal the applications of a new potential therapeutic strategy, but also to clarify the role of NO itself in clinical situations.