We have recently identified nitric oxide (NO)‐dependent antioxidant defense system underlying the resistance of oxidative myofibers to catabolic muscle wasting. To further ascertain the function of this defense system in vivo, we subjected mice to dexamethasone (Dex) injection with/without systemic administration of NO donor S‐nitrosoglutathione (GSNO). We show that Dex induced muscle atrophy and increased E3 ligases MAFbx/atrogin‐1 mRNA along with reduction of extracellular superoxide dismutase (EcSOD) protein in glycolytic muscles, which could be prevented by GSNO. Consistent with the hypothesis that EcSOD is important in maintaining muscle mass and function against cachexia, we observed that Dex‐induced muscle atrophy could be significantly attenuated by electric pulse‐mediated gene transfer of EcSOD and in muscle‐specific EcSOD transgenic mice [muscle creatine kinase (MCK)‐EcSOD]. Importantly, when MCK‐EcSOD mice were crossbred with cardiac‐specific calsequstrin [α‐myosin heavy chain (α‐MHC)‐CSQ] mice, a genetic model of chronic heart failure, they presented significant attenuation of catabolic muscle wasting with well‐preserved whole body muscle strength and exercise tolerance. These findings strongly support the functional importance of EcSOD in protecting against cachexia‐induced muscle wasting and loss of function.