Duchenne muscular dystrophy (DMD) is a systemic progressive muscular disease caused by frame‐disrupting mutations in the DMD gene. Although exon‐skipping antisense oligonucleotides (AOs) are clinically approved and can correct DMD, insufficient muscle delivery limits efficacy. If AO activity can be enhanced by safe dietary supplements, clinical trials for efficacy can be undertaken rapidly to benefit patients. We showed previously that intravenous glycine enhanced phosphorodiamidate morpholino oligomer (PMO) delivery to peripheral muscles in mdx mice. Here, we demonstrate that the combination of oral glycine and metformin with intravenous PMO enhances PMO activity, dystrophin restoration, extends lifespan, and improves body‐wide function and phenotypic rescue of dystrophin /utrophin double knock‐out (DKO) mice without any overt adverse effects. The DKO mice treated with the combination without altering the approved administration protocol of PMO show improved cardio‐respiratory and behavioral functions. Metformin and glycine individually are ineffective in DMD patients, but the combination of PMO with clinically‐approved oral glycine and metformin might improve the efficacy of the treatment also in DMD patients. Our data suggest that this combination therapy might be an attractive therapy for DMD and potentially other muscle diseases requiring systemic treatment with AOs. Synopsis The combination of oral glycine and metformin with clinically approved intravenous DMD exon‐skipping antisense oligonucleotides (AOs) enhances AO activity, dystrophin restoration, extends lifespan, and improves body‐wide function and phenotypic rescue of dystrophin/utrophin double knock‐out (DKO) mice. Oral glycine augments efficacy of intravenous exon‐skipping PMO therapy in mdx and DKO mice. Oral glycine and metformin with intravenous PMO enhances PMO activity, dystrophin restoration, extends lifespan, and improves body‐wide function and phenotypic rescue of dystrophic DKO mice without any overt adverse effects, most notably in the heart muscle. The DKO mice treated with repurposed clinically‐approved glycine and metformin without altering the approved intravenous administration protocol of PMO results in improved cardio‐respiratory and behavioral functions. The combination of oral glycine and metformin with clinically approved intravenous DMD exon‐skipping antisense oligonucleotides (AOs) enhances AO activity, dystrophin restoration, extends lifespan, and improves body‐wide function and phenotypic rescue of dystrophin/utrophin double knock‐out (DKO) mice.