Nitric oxide (NO) is a gaseous biocompatible radical molecule with demonstrated biomedical and antimicrobial benefits. Developing adaptable, long-lasting delivery systems for NO has become an essential goal for both combating resistant bacterial growth and providing sustained medical benefits. Silsesquioxane (SQ)-based organo-gels were chosen and synthesized as robust, tunable NO-release platforms. These highly stable SQ gel frameworks, composed of silicon–oxygen backbones with variable R-groups, exhibited high porosity and surface area, and offered chemical versatility, enabling control over NO loading and release. 3-Mercaptopropyl groups were utilized as sulfur-based NO-releasing substituents (-RSNOs), with additional R-groups capable of altering accessibility to RSNO sites through hydrophobicity and steric hindrance. The NO release profile, rate, and duration from the functionalized gels were also tailored by adjusting the number of RSNO sites in the elastomeric system, thereby enabling a customizable release profile. This combination of NO-releasing silsesquioxanes with silicone elastomers yields composite materials that are integratable into biomedical applications, offering NO release up to 40 days within modeled physiological conditions in PBS buffer.