Background Surgical treatment of peripheral artery disease, even if successful, does not prevent reoccurrence. Under these conditions, increased oxidative stress is a crucial determinant of tissue damage. Given its reported antioxidant effects, we investigated the potential of unacylated‐ghrelin (Un AG ) to reduce ischemia‐induced tissue damage in a mouse model of peripheral artery disease . Methods and Results We show that Un AG but not acylated ghrelin ( AG ) induces skeletal muscle regeneration in response to ischemia via canonical p38/mitogen‐actived protein kinase signaling Un AG protected against reactive oxygen species–induced cell injuries by inducing the expression of superoxide dismutase‐2 ( SOD ‐2) in satellite cells. This led to a reduced number of infiltrating CD 68 + cells and was followed by induction of the myogenic process and a reduction in functional impairment. Moreover, we found that miR‐221/222, previously linked to muscle regeneration processes, was up‐regulated and negatively correlated with p57 Kip2 expression in Un AG ‐treated mice. Un AG , unlike AG , promoted cell‐cycle entry in satellite cells of mice lacking the genes for ghrelin and its receptor ( GHSR 1a). Un AG ‐induced p38/mitogen‐actived protein kinase phosphorylation, leading to activation of the myogenic process, was prevented in SOD ‐2–depleted SC s. By si RNA technology, we also demonstrated that SOD ‐2 is the antioxidant enzyme involved in the control of miR‐221/222–driven posttranscriptional p57 Kip2 regulation. Loss‐of‐function experiments targeting miR‐221/222 and local pre–miR‐221/222 injection in vivo confirmed a role for miR‐221/222 in driving skeletal muscle regeneration after ischemia. Conclusions These results indicate that Un AG ‐induced skeletal muscle regeneration after ischemia depends on SOD ‐2–induced miR‐221/222 expression and highlight its clinical potential for the treatment of reactive oxygen species–mediated skeletal muscle damage.