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Summary Genetic deficiency of dystrophin leads to disability and premature death in Duchenne muscular dystrophy (DMD), affecting the heart as well as skeletal muscle. Here, we report that clinical-stage cardiac progenitor cells, known as cardiosphere-derived cells (CDCs), improve cardiac and skeletal myopathy in the mdx mouse model of DMD. Injection of CDCs into the hearts of mdx mice augments cardiac function, ambulatory capacity, and survival. Exosomes secreted by human CDCs reproduce the benefits of CDCs in mdx mice and in human induced pluripotent stem cell-derived Duchenne cardiomyocytes. Surprisingly, CDCs and their exosomes also transiently restored partial expression of full-length dystrophin in mdx mice. The findings further motivate the testing of CDCs in Duchenne patients, while identifying exosomes as next-generation therapeutic candidates., Graphical Abstract, Highlights • CDCs improve cardiac and skeletal myopathy in the mdx mouse model of DMD • CDC exosomes reproduce the benefits of CDCs • CDCs and their exosomes transiently restored partial expression of dystrophin, In this article, Marbán and colleagues show that exosomes mediate benefits of cell therapy in mouse and human models of Duchenne muscular dystrophy.