Cancer, congestive heart failure, chronic obstructive pulmonary disease, type 2 diabetes and aging induce skeletal muscle atrophy. These diseases and aging promote the formation of reactive oxygen species (ROS), which in turn regulate catabolic pathways involved in muscle atrophy. The first line of antioxidant defense system from ROS is comprised of superoxide dismutase (SOD), which scavenges superoxide (O2•−) to produce the less reactive hydrogen peroxide (H2O2). Mammalian skeletal muscle expresses cytosolic copper/zinc-containing SOD (CuZnSOD or SOD1), manganese SOD (MnSOD or SOD2), and extracellular SOD (EcSOD or SOD3). In this review, we provide an overview of 1) oxidative stress and antioxidants, 2) EcSOD ameliorates skeletal muscle abnormalities, cachexia, and exercise intolerance, 3) muscle-derived EcSOD protects against organ dysfunction, and 4) role of the Keap1-Nrf2 signaling pathway in the regulation of antioxidant defense system.