Duchenne muscular dystrophy (DMD) is a rare and devastating genetic disorder, whose management is still a major challenge, despite progress in genetic and pharmacological disease-modifying treatments have been made. Mitochondrial dysfunctions contribute to DMD, however, there are no effective mitochondrial therapies for DMD. SIRT1 is a NAD+-dependent class III histone deacetylase that controls several key processes and whose impairment is involved in determining mitochondrial dysfunction in DMD. In addition to well-known resveratrol, other potent selective activators of SIRT1 exist, with better pharmacokinetics properties. Among these, SRT2104 is the most promising and advanced in clinical studies. Here we evaluate the impact of SRT2104 in reshaping muscle proteome and acetylome profiles, highlighting the drug as an attractive exercise mimetic for the treatment of DMD. Overall, our data suggest SRT2104 as a possible therapeutic candidate to successfully counteract the progression of the dystrophic phenotype in DMD.