There is evidence that nitric oxide (NO) plays a critical role in skeletal muscle. In Duchenne muscular dystrophy (DMD) patients and the mdx mouse model of DMD, dystrophin deficiency causes a decrease and mislocalization of muscle-specific neuronal nitric oxide synthase (nNOSμ), leading to a variety of functional impairments such as muscle ischemia and compromised myogenesis. Previous studies have shown that NO donation associated with anti-inflammatory action showed beneficial effects in dystrophic mouse models. In this study, we have investigated the effects of naproxcinod, an NO donating naproxen, on skeletal and cardiac muscle function in mdx mice. 4-week-old mdx mice were orally treated for 9 months with three different doses of naproxcinod (10, 21 and 41 mg/kg/day) compared with 0.9 mg/kg of prednisolone. Functional and behavioral parameters using a grip strength meter and open field digiscan were measured at 3, 6, and 9 months of treatment using SOPs developed by TREAT-NMD. Additionally, in vitro EDL force contraction, optical imaging of inflammation, echocardiography and blood pressure were evaluated at the 9 months prior to sacrifice. Naproxcinod treatment at 10 and 21 mg/kg resulted in significant improvements in hindlimb grip strength as well as approximately a 25–30% decrease in inflammation in fore and hind limbs measured by in vivo optical imaging in mdx mice. Naproxcinod induced significant improvements in heart function as evidenced by ameliorated fraction shortening and ejection fraction measured using echocardiography along with improvements in systolic blood pressure. Moreover, the long term detrimental effects of prednisolone typically observed in mdx skeletal and heart function were not observed at the effective doses of naproxcinod. In conclusion, naproxcinod seems to have significant potential as a safe therapeutic option for the treatment of muscular dystrophies.