Aging is a process that represents the accumulation of changes in organism overtime. In biological level, accumulations of molecular and cellular damage in aging lead to an increasing risk of diseases like sarcopenia. Sarcopenia reduces mobility, leads to fall-related injuries, and diminishes life quality. Thus, it is meaningful to find out novel therapeutic strategies for sarcopenia intervention that may help the elderly maintain their functional ability. Oxidative damage-induced dysfunctional mitochondria are considered as a culprit of muscle wasting during aging. Herein, we aimed to demonstrate whether myricanol (MY) protects aged mice against muscle wasting through alleviating oxidative damage in mitochondria and identify the direct protein target and its underlying mechanism. We discovered that MY protects aged mice against the loss of muscle mass and strength through scavenging reactive oxygen species accumulation to rebuild the redox homeostasis. Taking advantage of biophysical assays, peroxiredoxin 5 was discovered and validated as the direct target of MY. Through activating peroxiredoxin 5, MY reduced reactive oxygen species accumulation and damaged mitochondrial DNA in C2C12 myotubes. Our findings provide an insight for therapy against sarcopenia through alleviating oxidative damage-induced dysfunctional mitochondria by targeting peroxiredoxin 5, which may contribute an insight for healthy aging.