Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD) are rare X-linked inherited neuromuscular disorders caused by genetic mutations resulting in the loss of the dystrophin protein. Steroids moderately slow disease progression, and therapies including exon-skipping antisense oligonucleotides (ASOs) and mini/micro-dystrophin expression only partially improve symptoms of a minority of DMD patients to the less severe BMD form, and there are no treatment for late stage BMD and DMD patients. There is thus an urgent need for novel therapeutic avenues for treating BMD and DMD. A number of pathological manifestations in DMD/BMD muscle have been documented, including impaired mitochondrial function, fat accumulation, inflammation, fibrosis, and cell death resulting in skeletal muscle wasting. Additionally, DMD/BMD patients suffer from dilated cardiomyopathy and heart failure. However, the molecular mechanisms underpinning these skeletal muscle and cardiac pathologies have not been elucidated. Here, we show that a microRNA, miR-128-3p, is elevated upon dystrophin loss, and represents a crucial contributor to skeletal and cardiac muscle pathologies in DMD animal models. ASO targeting of miR-128-3p dramatically mitigated muscle weakness and exercise incapacity and improved mitochondrial health and other muscle pathologies in the mdx5cv DMD mouse model. Importantly, anti-miR-128-3p ASO treatment in DMDY/- pigs significantly ameliorated cardiac insufficiency, markedly improving left ventricular (LV) fractional shortening and LV ejection fraction. We also observed improved markers of cardiac regeneration by single nucleus RNA-seq. Mechanistically, our studies show that miR-128-3p represents a key regulator of mitochondrial metabolism in skeletal muscle through modulation of the expression of a number of proteins implicated in DMD, such as PGC-1a, SIRT1, AMPKa2, CPT1b and PPARa. Taken together, our data suggest that miR-128-3p plays a critical role in the pathogenesis of skeletal and cardiac muscle dysfunction in DMD. Hence, anti-miR-128-3p represents an attractive target for highly potent and specific ASO therapeutics for the treatment of DMD and BMD.