Staphylococcus aureus (SA) is a leading cause of both superficial and invasive infections in community and hospital settings, frequently resulting in chronic refractory disease. It is imperative that innovative therapeutics to which the bacteria are unlikely to evolve resistance be developed to curtail associated morbidity and mortality and ultimately improve our capacity to treat these infections. In this study, a previously unreported nitric oxide (NO)-releasing nanoparticle technology is applied to the treatment of methicillin-resistant SA (MRSA) wound infections. The results show that the nanoparticles exert antimicrobial activity against MRSA in a murine wound model. Acceleration of infected wound closure in NO-treated groups was clinically shown compared with controls. The histology of wounds revealed that NO nanoparticle treatment decreased suppurative inflammation, minimal bacterial burden, and less collagen degradation, providing potential mechanisms for biological activity. Together, these data suggest that these NO-releasing nanoparticles have the potential to serve as a novel class of topically applied antimicrobials for the treatment of cutaneous infections and wounds.